Method of treating cancer

ABSTRACT

The present invention relates to methods of treating cancer using a combination of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at least two therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase. The invention also relates to methods of preparing such compositions.

BACKGROUND OF THE INVENTION

The present invention relates to methods of treating cancer using acombination of an antineoplastic agent and a compound which is aninhibitor of a prenyl-protein transferase.

Chemotherapy, the systematic administration of antineoplastic agentsthat travel throughout the body via the blood circulatory system, alongwith and often in conjunction with surgery and radiation treatment, hasfor years been widely utilized in the treatment of a wide variety ofcancers. Unfortunately, the available chemotherapeutic drugs often failpatients because they kill many healthy cells and thus bring on seriousside effects that limit the doses physicians can administer.

Prenylation of proteins by intermediates of the isoprenoid biosyntheticpathway represents a class of post-translational modification (Glomset,J. A., Gelb, M. H., and Farnsworth, C. C. (1990). Trends Biochem. Sci.15, 139-142; Maltese, W. A. (1990). FASEB J. 4, 3319-3328). Thismodification typically is required for the membrane localization andfunction of these proteins. Prenylated proteins share characteristicC-terminal sequences including CaaX (C, Cys; a, usually aliphatic aminoacid; X, another amino acid), XXCC, or XCXC. Three post-translationalprocessing steps have been described for proteins having a C-terminalCaaX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon(geranylgeranyl) isoprenoid to the Cys residue, proteolytic cleavage ofthe last 3 amino acids, and methylation of the new C-terminalcarboxylate (Cox, A. D. and Der, C. J. (1992a). Critical Rev.Oncogenesis 3:365-400; Newman, C. M. H. and Magee, A. I. (1993).Biochim. Biophys. Acta 1155:79-96). Some proteins may also have a fourthmodification: palmitoylation of one or two Cys residues N-terminal tothe farnesylated Cys. While some mammalian cell proteins terminating inXCXC are carboxymethylated, it is not clear whether carboxy methylationfollows prenylation of proteins terminating with a XXCC motif (Clarke,S. (1992). Annu. Rev. Biochem. 61, 355-386). For all of the prenylatedproteins, addition of the isoprenoid is the first step and is requiredfor the subsequent steps (Cox, A. D. and Der, C. J. (1992a). CriticalRev. Oncogenesis 3:365-400; Cox, A. D. and Der, C. J. (1992b) CurrentOpinion Cell Biol. 4:1008-1016).

Three enzymes have been described that catalyze protein prenylation:farnesyl-protein transferase (FPTase), geranylgeranyl-proteintransferase type I (GGPTase-I), and geranylgeranyl-protein transferasetype-II (GGPTase-II, also called Rab GGPTase). These enzymes are foundin both yeast and mammalian cells (Clarke, 1992; Schafer, W. R. andRine, J. (1992) Annu. Rev. Genet. 30:209-237). Each of these enzymesselectively uses farnesyl diphosphate (FPP) or geranyl-geranyldiphosphate as the isoprenoid donor and selectively recognizes theprotein substrate. FPTase farnesylates CaaX-containing proteins that endwith Ser, Met, Cys, Gln or Ala. For FPTase, CaaX tetrapeptides comprisethe minimum region required for interaction of the protein substratewith the enzyme. The enzymological characterization of these threeenzymes has demonstrated that it is possible to selectively inhibit onewith little inhibitory effect on the others (Moores, S. L., Schaber, M.D., Mosser, S. D., Rands, E., O'Hara, M. B., Garsky, V. M., Marshall, M.S., Pompliano, D. L., and Gibbs, J. B., J. Biol. Chem., 266:17438(1991), U.S. Pat. No. 5,470,832).

The prenylation reactions have been shown genetically to be essentialfor the function of a variety of proteins (Clarke, 1992; Cox and Der,1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993;Schafer and Rine, 1992). This requirement often is demonstrated bymutating the CaaX Cys acceptors so that the proteins can no longer beprenylated. The resulting proteins are devoid of their centralbiological activity. These studies provide a genetic “proof ofprinciple” indicating that inhibitors of prenylation can alter thephysiological responses regulated by prenylated proteins.

The Ras protein is part of a signalling pathway that links cell surfacegrowth factor receptors to nuclear signals initiating cellularproliferation. Biological and biochemical studies of Ras action indicatethat Ras functions like a G-regulatory protein. In the inactive state,Ras is bound to GDP. Upon growth factor receptor activation, Ras isinduced to exchange GDP for GTP and undergoes a conformational change.The GTP-bound form of Ras propagates the growth stimulatory signal untilthe signal is terminated by the intrinsic GTPase activity of Ras, whichreturns the protein to its inactive GDP bound form (D. R. Lowy and D. M.Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Activation of Rasleads to activation of multiple intracellular signal transductionpathways, including the MAP Kinase pathway and the Rho/Rac pathway(Joneson et al., Science 271:810-812).

Mutated ras genes are found in many human cancers, including colorectalcarcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Theprotein products of these genes are defective in their GTPase activityand constitutively transmit a growth stimulatory signal.

The Ras protein is one of several proteins that are known to undergopost-translational prenylation. Farnesyl-protein transferase utilizesfarnesyl pyrophosphate to covalently modify the Cys thiol group of theRas CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al.,Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci. USA,87:7541-7545 (1990)).

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a “CAAX” or “Cys-Aaa²-Aaa²-Xaa” box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)).

Other farnesylated proteins include the Ras-related GTP-binding proteinssuch as RhoB, fungal mating factors, the nuclear lamins, and the gammasubunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994)have identified a peroxisome associated protein Pxf which is alsofarnesylated. James, et al., have also suggested that there arefarnesylated proteins of unknown structure and function in addition tothose listed above.

Inhibitors of farnesyl-protein transferase have been described in twogeneral classes. The first class includes analogs of FPP, while thesecond is related to protein substrates (e.g., Ras) for the enzyme. Thepeptide derived inhibitors that have been described are generallycysteine containing molecules that are related to the CAAX motif that isthe signal for protein prenylation. (Schaber et al., ibid.; Reiss et.al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors mayinhibit protein prenylation while serving as alternate substrates forthe farnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)).

Mammalian cells express four types of Ras proteins (H-, N-, K4A-, andK4B-Ras) among which K-Ras4B is the most frequently mutated form of Rasin human cancers. Inhibition of farnesyl-protein transferase has beenshown to block the growth of H-ras-transformed cells in soft agar and tomodify other aspects of their transformed phenotype. It has also beendemonstrated that certain inhibitors of farnesyl-protein transferaseselectively block the processing of the H-Ras oncoproteinintracellularly (N. E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has beenshown that an inhibitor of farnesyl-protein transferase blocks thegrowth of H-ras-dependent tumors in nude mice (N. E. Kohl et al., Proc.Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression ofmammary and salivary carcinomas in H-ras transgenic mice (N. E. Kohl etal., Nature Medicine, 1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Inhibition of farnesyl pyrophosphate biosynthesis byinhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. Because prenyl pyrophosphates are intermediates in manybiosynthetic processes, direct inhibition of a prenyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

It is the object of the instant invention to provide a composition thatcomprises an antineoplastic agent and a prenyl-protein transferaseinhibitor whose therapeutic effect in combination may allow use of theantineoplastic agent at a dose which is lower than the dose of theantineoplastic agent if it was used alone and may therefore amelioratesome of the unwanted side effects normally associated with traditionalchemotherapy.

A pharmaceutically effective combination of an antineoplastic agent anda prenyl-protein transferase inhibitor are used in the present inventionto treat cancer, such as in tumor cells that are less susceptable totreatment by antagonist of the antineoplastic agent or prenyl-proteintransferase inhibitor when administered alone.

SUMMARY OF THE INVENTION

A method of treating cancer is disclosed which is comprised ofadministering to a mammalian patient in need of such treatment aneffective amount of a combination of an antineoplastic agent and aprenyl-protein transferase inhibitor. Preferably an antineoplastic agentand a farnesyl protein transferase inhibitor are used in such acombination.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on MCF-7 Cells:

Cell proliferation of MCF-7 cells (ATCC HTB-22; J. Natl. Cancer Inst.(Bethesda) 51:1409-1416 (1973)) which were preincubated for one day inthe presence or absence of 0.02 μM Compound A, followed by a 4 hourtreatment with various concentrations of paclitaxel. After the treatmentwith paclitaxel, the cell were incubated for 7 additional days in thepresence or absence of 0.02 μM Compound A. See Protocol B in the “Invitro growth inhibition of human tumor cells assay.”

FIG. 2: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on MDA MB-468 Cells:

Cell proliferation of MDA MB-468 cells (ATCC HTB-132; In Vitro(Rockville) 14:911-915 (1978)) which were treated with variousconcentrations of paclitaxel for 4 hours. After the treatment withpaclitaxel the cell were incubated for 9 days in the absence or presenceof 0.2 μM or 0.5 μM Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 2A: Effect of a Farnesyl-Protein Transferase Inhibitor incombination with Paclitaxel on MDA MB-468 Cells:

Cell proliferation of MDA MB-468 cells which were pre-incubated in theabsence or presence of 0.2 μM or 0.5 μM Compound A. At the end of 24hours the cells were also exposed to various concentrations ofpaclitaxel for 4 hours. After the treatment with paclitaxel the cellwere washed and incubated for 8 days in the presence of thepre-incubation concentration of Compound A. See Protocol B in the “Invitro growth inhibition of human tumor cells assay.”

FIG. 2B: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on MDA MB-468 Cells:

Cell proliferation of MDA MB-468 cells were exposed to variousconcentrations of paclitaxel in the absence or presence of 0.2 μM or 0.5μM Compound A for 6 days. See Protocol C in the “In vitro growthinhibition of human tumor cells assay.”

FIGS. 3A and 3B: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on DU145 Cells:

DU145 human prostate cancer cells (ATCC HTB-81, Cancer Res. 37:4049-4058(1977), Int. J. Cancer, 21:274-281 (1978)), which were treated for four(4) hours with paclitaxel and then washed, were treated inanchorage-dependent and -independent growth assays in the absence orpresence of 0.2 μM, 2 μM or 20 μM Compound A. For FIG. 3A, whichrepresents the effect of a combination of paclitaxel and Compound A onanchorage-independent growth, see Protocol D-1 in the “In vitro growthinhibition of human tumor cells assay.” For FIG. 3B, which representsthe effect of a combination of paclitaxel and Compound A onanchorage-dependent growth, see Protocol D-2 in the “In vitro growthinhibition of human tumor cells assay.”

FIGS. 4 and 4A-4L: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on the Cell Cycle of MCF-7 Cells:

MCF-7 cells were preincubated for one day, followed by a 24 hourtreatment with various concentrations of paclitaxel in the presence orabsence of 1μM Compound A. The DNA contents of the cells were thenassessed according to the protocol described in “In vitro cell cycleassay.” The cell population having various DNA quantities was thendetermined and analyzed graphically. FIG. 4 shows a composite of 12 cellDNA-content histograms representing the various treatment combinations.FIGS. 4A-4L show the individual histograms in greater detail. FIGS.4A-4F show the histograms of the treatment in the absence of Compound Aand with increasing concentrations of paclitaxel (the left column ofFIG. 4). FIGS. 4G-4L show the histograms of the treatment in thepresence of 1 μM of Compound A and with increasing concentrations ofpaclitaxel (the right column of FIG. 4). The addition of Compound Aincreases the molar potency with which paclitaxel causes G₂/M phasearrest in MCF-7 cells.

FIG. 5: Specific Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on the Cell Cycle of MCF-7 Cells:

The cells which contained the doubled DNA content from the assaydescribed above for FIGS. 4 and 4A-4L were analyzed to determine whichparticular cell cycle phase was affected by the addition of Compound Ato the paclitaxel treatment. Thus, aliquots of the cell populations forthe various paclitaxel/Compound A treatments were. fixed in 3%paraformaldehyde for 10 minutes, washed in PBS and stained in 24 μg/mlbis-benzimide in PBS. Mitotic cells were distinguished from interphasecells under fluorescence microscopy by characteristic chromatincondensation and mitotic indices were obtained by manual counting of1000 cells in each experimental treatment group. The results of thosecounts are shown in FIG. 5. The results show that the enhancement inblockage at the G₂/M phase of the cell cycle is largely due to an effecton the M-phase.

FIG. 6: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on DU145 Cells:

Cell proliferation of DU145 cells which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 30,000/6well plate. After the treatment with paclitaxel, the cells wereincubated for 5 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 7: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on T47D Cells:

Cell proliferation of T47D cells which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 20,000/6well plate. After the treatment with paclitaxel, the cells wereincubated for 10 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 8: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on MDA-231 Cells:

Cell proliferation of MDA-231 cells (ATCC HTB-26, J. Natl. Cancer Inst.(Bethesda) 53:661-674 (1974)) which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 5,000/6 wellplate. After the treatment with paclitaxel, the cells were incubated for7 days in the absence or presence of various concentrations of CompoundA. See Protocol A in the “In vitro growth inhibition of human tumorcells assay.”

FIG. 9: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on SK-OV-3 Cells:

Cell proliferation of SK-OV-3 cells (ATCC HTB-77, J. Natl. Cancer Inst.(Bethesda) 58:209-214 (1977)) which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 20,000/6well plate. After the treatment with paclitaxel, the cells wereincubated for 4 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 10: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on A549 Cells:

Cell proliferation of A549 cells (ATCC CCL-185, J. Natl. Cancer Inst.(Bethesda) 51:1417-1423 (1973)) which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 25,000/6well plate. After the treatment with paclitaxel, the cells wereincubated for 3 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 11: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on SkBr3 Cells:

Cell proliferation of SkBr3 cells (ATCC HTB-30) which were treated withvarious concentrations of paclitaxel for 4 hours. Cells were seeded40,000/6 well plate. After the treatment with paclitaxel, the cells wereincubated for 6 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 12: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Paclitaxel on PC3 Cells:

Cell proliferation of PC3 cells (ATCC CRL-1435; Invest. Urol., 17:16-23(1979); Cancer Res. 40: 524-534 (1980)) which were treated with variousconcentrations of paclitaxel for 4 hours. Cells were seeded 25,000/6well plate. After the treatment with paclitaxel, the cells wereincubated for 5 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 13: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with ara-C on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of ara-C for 4 hours. Cells were seeded 20,000/6 wellplate. After the treatment with ara-C, the cells were incubated for 7days in the absence or presence of various concentrations of Compound A.See Protocol A in the “In vitro growth inhibition of human tumor cellsassay.”

FIG. 14: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Vinblastine on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of vinblastine for 4 hours. Cells were seeded 20,000/6well plate. After the treatment with vinblastine the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 15: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with 5-fluorouracil on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of 5-fluorouracil for 4 hours. Cells were seeded 20,000/6well plate. After the treatment with 5-fluorouracil, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 16: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Colchicine on MDA-468 Cells:

Cell proliferation of MDA-468 cells which were treated with variousconcentrations of colchicine in the absence or presence of variousconcentrations of Compound A for 24 hours. Cells were seeded 20,000/6well plate. After the treatment with colchicine and Compound A, thecells were washed and then were incubated for 8 days in the absence orpresence of various concentrations of Compound A. See Protocol C in the“In vitro growth inhibition of human tumor cells assay.”

FIG. 17: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Vinblastine on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of vinblastine for 7 days in the absence or presence ofvarious concentrations of Compound A. Cells were seeded 10,000/6 wellplate. See Protocol B in the “In vitro growth inhibition of human tumorcells assay.”

FIG. 18: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Doxorubicin on MDA-468 Cells:

Cell proliferation of MDA-468 cells which were treated with variousconcentrations of doxorubicin for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with doxorubicin, the cells wereincubated for 10 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 19: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Doxorubicin on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of doxorubicin for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with doxorubicin, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 20: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Cisplatinum on MDA-468 Cells:

Cell proliferation of MDA-468 cells which were treated with variousconcentrations of cisplatinum for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with cisplatinum, the cells wereincubated for 10 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 21: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Cisplatinum on MCF-7 Cells:

Cell proliferation of MCF-7 cells which were treated with variousconcentrations of cisplatinum for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with cisplatinum, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 22: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Vinblastine on MDA-468 Cells:

Cell proliferation of MDA-468 cells which were treated with variousconcentrations of vinblastine for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with vinblastine, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 23: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Desoxyepithilone A on MDA-468 Cells:

Cell proliferation of MDA-468 cells which were treated with variousconcentrations of desoxyepithilone A for 4 hours. Cells were seeded20,000/6 well cluster. After the treatment with desoxyepithilone A, thecells were incubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 24: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Epithilone A on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of epithilone A for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with epithilone A, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 25: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Epithilone B on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of epithilone B for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with epithilone B, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 26: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Desoxyepithilone A on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of desoxyepithilone A for 4 hours. Cells were seeded20,000/6 well cluster. After the treatment with desoxyepithilone A, thecells were incubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 27: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Desoxyepithilone B on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of desoxyepithilone B for 4 hours. Cells were seeded20,000/6 well cluster. After the treatment with desoxyepithilone B, thecells were incubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 28: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Etoposide on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of etoposide for 4 hours. Cells were seeded 20,000/6 wellcluster. After the treatment with etoposide, the cells were incubatedfor 7 days in the absence or presence of various concentrations ofCompound A. See Protocol A in the “In vitro growth inhibition of humantumor cells assay.”

FIG. 29: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Doxorubicin on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of doxorubicin for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with doxorubicin, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 30: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Estramustine on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of estramustine for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with estramustine, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 31: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Cisplatinum on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousconcentrations of cis-platinum for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with cis-platinum, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 32: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with Bicalutamide on LNCaP Cells:

Cell proliferation of LNCaP cells which were treated with variousconcentrations of bicalutamide for 4 hours. Cells were seeded 20,000/6well cluster. After the treatment with bicalutamide, the cells wereincubated for 7 days in the absence or presence of variousconcentrations of Compound A. See Protocol A in the “In vitro growthinhibition of human tumor cells assay.”

FIG. 33: Effect of a Farnesyl-Protein Transferase Inhibitor inCombination with γ-Radiation on DU 145 Cells:

Cell proliferation of DU 145 cells which were treated with variousamounts of γ-radiation. Cells were seeded 20,000/6 well cluster. Cellswere either pretreated with 20 mM Compound A, treated with 20 mMCompound A after irradiation or not treated with an FTI.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating cancer which iscomprised of administering to a mammalian patient in need of suchtreatment an effective amount of a combination of an antineoplasticagent and a prenyl-protein transferase inhibitor. The present method oftreating cancer by simultaneously inhibiting protein prenylation andinterfering with DNA replication and/or inducing apoptosis offersadvantages over previously disclosed methods which utilize aprenyl-protein transferase inhibitor or an antineoplastic agent alone,in that the inhibitory activity and dosage of the instant combination ofinhibitors of prenyl-protein transferase and anti-neoplastic agents canbe individually varied depending on the nature of the cancer cells to betreated. Any compounds which act as an antineoplastic agent and anycompounds which inhibit prenyl-protein transferase can be used in. theinstant method. Preferably the compounds utilized in the instantcombination are an antineoplastic agent and a farnesyl-proteintransferase inhibitor. When practicing the present method theantineoplastic agent and the inhibitor of prenyl-protein transferase maybe administered either sequentially in any order or simultaneously.

It is anticipated that the therapeutic effect of the instantcompositions may be achieved with smaller amounts of the antineoplasticagents and prenyl-protein transferase inhibitors than would be requiredif such antineoplastic agents and a prenyl-protein transferaseinhibitors were administered alone, thereby avoiding anynon-mechanism-based adverse toxicity effects which might result fromadministration of an amount of the single antineoplastic agent orprenyl-protein transferase inhibitor sufficient to achieve the sametherapeutic effect. It is also anticipated that the instant compositionswill achieve a synergistic therapeutic effect or will exhibit unexpectedtherapeutic advantage over the effect of any of the component compoundsif administered alone.

As used herein the term an antineoplastic agent refers to compoundswhich either prevent cancer cells from multiplying by interfering withthe cell's ability to replicate DNA or induce apoptosis in the cancerouscells.

The term prenyl-protein transferase inhibiting compound refers tocompounds which antagonize, inhibit or counteract the expression of thegene coding a prenyl-protein transferase or the activity of the proteinproduct thereof.

The term farnesyl protein transferase inhibiting compound likewiserefers to compounds which antagonize, inhibit or counteract theexpression of the gene coding farnesyl-protein transferase or theactivity of the protein product thereof.

The term selective as used herein refers to the inhibitory activity ofthe particular compound against a prenyl-protein transferase activity orfarnesyl-protein transferase activity. Preferably, for example, aselective inhibitor of farnesyl-protein transferase exhibits at least 20times greater activity against farnesyl-protein transferase whencomparing its activity against another receptor or enzymatic activity,respectively. More preferably the selectivity is at least 100 times ormore.

The extent of selectivity of the two inhibitors that comprise the methodof the instant invention may effect the advantages that the method oftreatment claimed herein offers over previously disclosed methods ofusing a single antineoplastic agent or prenyl-protein transferaseinhibitor for the treatment of cancer. In particular, use of twoindependent pharmaceutically active components that have complementary,essentially non-overlapping activities allows the person utilizing theinstant method of treatment to independently and accurately vary theinhibitory activity of the combination without having to synthesize asingle drug having a particular pharmaceutical activity profile.

The term “synergistic” as used herein means that the effect achievedwith the methods and compositions of this invention is greater than thesum of the effects that result from methods and compositions comprisingthe prenyl-protein transferase inhibitor and antineoplastic agent ofthis invention separately and in the amounts employed in the methods andcompositions hereof. Such synergy between the two active ingredientsenabling smaller doses to be given and preventing or delaying the buildup of multi-drug resistance.

The preferred therapeutic effect provided by the instant composition isthe treatment of cancer and specifically the inhibition of canceroustumor growth and/or the regression of cancerous tumors. Cancers whichare treatable in accordance with the invention described herein includecancers of the brain, breast, colon, genitourinary tract, lymphaticsystem, pancreas, rectum, stomach, larynx, liver, lung and prostate.More particularly, such cancers include histiocytic lymphoma, lungadenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small celllung cancers and neurological tumors.

The composition of this invention is also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the instant composition to amammal in need of such treatment. For example, a component of NF-1 is abenign proliferative disorder.

The composition of the instant invention is also useful in theprevention of restenosis after percutaneous transluminal coronaryangioplasty by inhibiting neointimal formation (C. Indolfi et al. Naturemedicine, 1:541-545(1995).

The instant composition may also be useful in the treatment andprevention of polycystic kidney disease (D. L. Schaffner et al. AmericanJournal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).

The pharmaceutical composition of this invention may be administered tomammals, preferably humans, either alone or, preferably, in combinationwith pharmaceutically acceptable carriers or diluents, optionally withknown adjuvants, such as alum, in a pharmaceutical composition,according to standard pharmaceutical practice. The compounds can beadministered orally or parenterally, including the intravenous,intramuscular, intraperitoneal, subcutaneous, rectal and topical routesof administration.

For oral use of a chemotherapeutic combination according to thisinvention, the selected combination or compounds may be administered,for example, in the form of tablets or capsules, or as an aqueoussolution or suspension. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch, and lubricatingagents, such as magnesium stearate, are commonly added. For oraladministration in capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions are required for oral use,the active ingredients are combined with emulsifying and suspendingagents. If desired, certain sweetening and/or flavoring agents may beadded. For intramuscular, intraperitoneal, subcutaneous and intravenoususe, sterile solutions of the active ingredient are usually prepared,and the pH of the solutions should be suitably adjusted and buffered.For intravenous use, the total concentration of solutes should becontrolled in order to render the preparation isotonic.

The combinations of the instant invention may also be co-administeredwith other well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated.

If formulated as a fixed dose, such combination products employ thecombinations of this invention within the dosage range described belowand the other pharmaceutically active agent(s) within its approveddosage range. Combinations of the instant invention may alternatively beused sequentially with known pharmaceutically acceptable agent(s) when amultiple combination formulation is inappropriate.

The instant invention encompasses a method of treatment wherein anantineoplastic agent and an inhibitor of prenyl-protein transferase areadministered simultaneously or sequentially. Thus, while apharmaceutical formulation comprising an antineoplastic agent and aninhibitor of prenyl-protein transferase may be advantageous foradministering the combination for one particular treatment, sequentialadministration of the components of the combination may be advantageousin another treatment. It is also understood that the instant combinationof antineoplastic agent and inhibitor of prenyl-protein transferase maybe used in conjunction with other methods of treating cancer and/ortumors, including radiation therapy and surgery.

Radiation therapy, including x-rays or gamma rays which are deliveredfrom either an externally applied beam or by implantation of tinyradioactive sources, may also be used in combination with an inhibitorof prenyl-protein transferase alone to treat cancer. The prenyl-proteintransferase inhibitors may either be administered concurrently with theradiation therapy or may be administered prior to the application of theradiation.

In a particularly useful example of the method comprises of combiningradiation therapy and administering an inhibitor of prenyl-proteintransferase, a farnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A);    is administered prior to the application of radiation therapy.

In another particularly useful example of the method comprises ofcombining radiation therapy and administering an inhibitor ofprenyl-protein transferase, a farnesyl-protein transferase inhibitorwhich is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;-   or a pharmaceutically acceptable salt thereof;    is administered prior to the application of radiation therapy.

In another particularly useful example of the method comprises ofcombining radiation therapy and administering an inhibitor ofprenyl-protein transferase, a farnesyl-protein transferase inhibitorwhich is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;-   or a pharmaceutically acceptable salt thereof;    is administered prior to the application of radiation therapy.

In another particularly useful example of the method comprises ofcombining radiation therapy and administering an inhibitor ofprenyl-protein transferase, a farnesyl-protein transferase inhibitorwhich is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;-   or a pharmaceutically acceptable salt thereof;    is administered prior to the application of radiation therapy.

In another particularly useful example of the method comprises ofcombining radiation therapy and administering an inhibitor ofprenyl-protein transferase, a farnesyl-protein transferase inhibitorwhich is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;-   or a pharmaceutically acceptable salt thereof;    is administered prior to the application of radiation therapy.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the combinations of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

When a combination according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

In one exemplary application, a suitable amount of an antineoplasticagent and a prenyl-protein transferase inhibitor are administered to amammal undergoing treatment for cancer. Administration occurs in anamount of each type of inhibitor of between about 0.1 mg/kg of bodyweight to about 60 mg/kg of body weight per day, preferably of between0.5 mg/kg of body weight to about 40 mg/kg of body weight per day. Aparticular therapeutic dosage that comprises the instant compositionincludes from about 0.01 mg to about 500 mg of an antineoplastic agentand from about 0.01 mg to about 500mg of a prenyl-protein transferaseinhibitor. Preferably, the dosage comprises from about 1 mg to about 100mg of an antineoplastic agent and from about 1 mg to about 100 mg of aprenyl-protein transferase inhibitor.

Examples of an antineoplastic agent include, in general,microtubule-stabilising agents (such as paclitaxel (also known asTaxol®), docetaxel (also known as Taxotere®), epothilone A, epothiloneB, desoxyepothilone A, desoxyepothilone B or their derivatives);microtubule-disruptor agents; alkylating agents, anti-metabolites; afusel poison; epidophyllotoxin; an antineoplastic enzyme; atopoisomerase inhibitor; procarbazine; mitoxantrone; platinumcoordination complexes; biological response modifiers and growthinhibitors; hormonal/anti-hormonal therapeutic agents and haematopoieticgrowth factors.

Example classes of antineoplastic agents include, for example, theanthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, the taxanes, the epothilones,discodermolide, the pteridine family of drugs, diynenes and thepodophyllotoxins. Particularly useful members of those classes include,for example, doxorubicin, carminomycin, daunorubicin, aminopterin,methotrexate, methopterin, dichloro-methotrexate, mitomycin C,porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosinearabinoside, podophyllotoxin or podo-phyllotoxin derivatives such asetoposide, etoposide phosphate or teniposide, melphalan, vinblastine,vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.Other useful antineoplastic agents include estramustine, cisplatin,carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide,melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate,trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11,topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindolederivatives, interferons and interleukins.

The preferred class of antineoplastic agents is the taxanes and thepreferred antineoplastic agent is paclitaxel.

Examples of farnesyl-protein transferase inhibiting compounds includethe following:

(a) a compound represented by formula (II-a) through (II-c):

or a pharmaceutically acceptable salt thereof,

-   R^(1a) and R^(1b) are independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, NO₂,        (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or        R¹¹OC(O)NR¹⁰—,    -   c) C₁-C₆ alkyl unsubstituted or substituted by aryl,        heterocyclyl, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, (R¹⁰)₂N—C(NR¹⁰)—,        R¹⁰C(O)—, R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)—NR¹⁰—;-   R² and R³ are independently selected from: H; unsubstituted or    substituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,    unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or    substituted aryl, unsubstituted or substituted heterocycle,    -   -   wherein the substituted group is substituted with one or            more of:-   R² and R³ are attached to the same C atom and are combined to form    —(CH₂)_(u)— wherein one of the carbon atoms is optionally replaced    by a moiety selected from: O, S(O)_(m), —NC(O)—, and —N(COR¹⁰)—;-   R⁴ and R⁵ are independently selected from H and CH₃; and any two of    R², R³, R⁴ and R⁵ are optionally attached to the same carbon atom;-   R⁶, R⁷ and R^(7a) are independently selected from: H; C₁₋₄ alkyl,    C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl,    arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:-   R⁶ and R⁷ may be joined in a ring;-   R⁷ and R^(7a) may be joined in a ring;-   R⁸ is independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, CN, NO₂, R¹⁰ ₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, N₃,        —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰— and    -   c) C₁-C₆ alkyl unsubstituted or substituted by aryl,        heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰OC(O)NH—, CN,        H₂N—C(NH)—, R¹⁰C(O)—, R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or R¹⁰OC(O)NH—;-   R⁹ is selected from:    -   a) hydrogen,    -   b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br,        R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C—(NR¹⁰)—,        R¹⁰C(O)—, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by perfluoroalkyl,        F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN,        (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or        R¹¹OC(O)NR¹⁰—;-   R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl and    aryl;-   R¹¹ is independently selected from C₁-C₆ alkyl and aryl;-   A¹ and A² are independently selected from: a bond, —CH═CH—, —C≡C—,    —C(O)—, —C(O)NR¹⁰, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,    —N(R¹⁰)S(O)₂—, or S(O)_(m);-   V is selected from:    -   a) hydrogen,    -   b) heterocycle,    -   c) aryl,    -   d) C₁-C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced        with a heteroatom selected from O, S, and N, and    -   e) C₂-C₂₀ alkenyl,        provided that V is not hydrogen if A¹ is S(O)_(m) and V is not        hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m);-   W is a heterocycle;-   X is —CH₂—, —C(═O)—, or —S(═O)_(m)—;-   Y is aryl, heterocycle, unsubstituted or substituted with one or    more of:    -   1) C₁₋₄ alkyl, unsubstituted or substituted with:        -   a) C₁₋₄ alkoxy,        -   b) NR⁶R⁷,        -   c) C₃₋₆ cycloalkyl,        -   d) aryl or heterocycle,        -   e) HO,        -   f) —S(O)_(m)R⁶, or        -   g) —C(O)NR⁶R⁷,    -   2) aryl or heterocycle,    -   3) halogen,    -   4) OR⁶,    -   5) NR⁶R⁷,    -   6) CN,    -   7) NO₂,    -   8) CF₃;    -   9) —S(O)_(m)R⁶,    -   10) —C(O)NR⁶R⁷, or    -   11) C₃-C₆ cycloalkyl;-   m is 0, 1 or 2;-   n is 0, 1, 2, 3 or 4;-   p is 0, 1, 2, 3 or 4;-   r is 0 to 5, provided that r is 0 when V is hydrogen;-   s is 0 or 1;-   t is 0 or 1;and-   u is 4 or 5;    with respect to formula (II-b):    or a pharmaceutically acceptable salt thereof,-   R^(1a), R^(1b), R¹⁰, R¹¹, m, R², R³, R⁶, R⁷, p, R^(7a), u, R⁸, A¹,    A², V, W, X, n, p, r, s, t and u are as defined above with respect    to formula (II-a);-   R⁴ is selected from H and CH₃;-   and any two of R², R³ and R⁴ are optionally attached to the same    carbon atom;-   R⁹ is selected from:    -   a) hydrogen,    -   b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C—(NR¹⁰)—,        R¹⁰C(O)—, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by perfluoroalkyl,        F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN,        (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or        R¹¹OC(O)NR¹⁰—;-   G is H₂ or O;-   Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl,    heteroarylsulfonyl, unsubstituted or substituted with one or more of    the following:    -   1) C₁₋₄ alkyl, unsubstituted or substituted with:        -   a) C₁₋₄ alkoxy,        -   b) NR⁶R⁷,        -   c) C₃₋₆ cycloalkyl,        -   d) aryl or heterocycle,        -   e) HO,        -   f) —S(O)_(m)R⁶, or        -   g) —C(O)NR⁶R⁷,    -   2) aryl or heterocyclc,    -   3) halogen,    -   4) OR⁶,    -   5) NR⁶R⁷,    -   6) CN,    -   7) NO₂,    -   8) CF₃;

9) —S(O)_(m)R⁶,

-   -   10) —C(O)NR⁶R⁷, or    -   11) C₃-C₆ cycloalkyl;        with respect to formula (II-c):        or a pharmaceutically acceptable salt thereof,

-   R^(1a), R^(1b), R¹⁰, R¹¹, m, R², R³, R⁶, R⁷, p, u, R^(7a), R⁸, A¹,    A², V, W, X, n, r and t are as defined above with respect to formula    (II-a);

-   R⁴ is selected from H and CH₃;    -   and any two of R², R³ and R⁴ are optionally attached to the same        carbon atom;

-   G is 0;

-   Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl,    heteroarylsulfonyl, unsubstituted or substituted with one or more of    the following:    -   1) C₁₋₄ alkyl, unsubstituted or substituted with:        -   a) C₁₋₄ alkoxy,        -   b) NR⁶R⁷,        -   c) C₃₋₆ cycloalkyl,        -   d) aryl or heterocycle,        -   e) HO,        -   f) —S(O)_(m)R⁶, or        -   g) —C(O)NR⁶R⁷,    -   2) aryl or heterocycle,    -   3) halogen,    -   4) OR⁶,    -   5) NR⁶R⁷,    -   6) CN,    -   7) NO₂,    -   8) CF₃;

9) —S(O)_(m)R⁶,

-   -   10) —C(O)NR⁶R⁷, or    -   11) C₃-C₆ cycloalkyl;        and

-   s is 1;

(b) a compound represented by formula (II-d):

wherein:

-   R^(1a) and R^(1b) are independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, R¹¹C(O)O—,        (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂,        or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted or substituted C₁-C₆ alkyl wherein the        substituent on the substituted C₁-C₆ alkyl is selected from        unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃,        —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;-   R², R³, R⁴ and R⁵ are independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹C(O)O—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted C₁-C₆ alkyl,    -   d) substituted C₁-C₆ alkyl wherein the substituent on the        substituted C₁-C₆ alkyl is selected from unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;-   R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selected    from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹C(O)O—, R¹⁰ ₂N—CNR¹⁰)—, CN, NO₂,        R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted C₁-C₆ alkyl,    -   d) substituted C₁-C₆ alkyl wherein the substituent on the        substituted C₁-C₆ alkyl is selected from unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—CNR¹⁰)—, CN,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;-   any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent    carbon atoms are combined to form a diradical selected from    —CH═CH—CH═CH—, —CH═CH—CH₂—, —(CH₂)₄— and —(CH₂)₃—;-   R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle,    aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,    unsubstituted or substituted with:-   R⁸ is independently selected from:    -   a) hydrogen,    -   b) aryl, substituted aryl, heterocycle, substituted heterocycle,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl,        F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰        ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,        and    -   c) C₁-C₆ alkyl unsubstituted or substituted by aryl,        cyanophenyl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NH—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃,        —N(R¹⁰)₂, or R¹⁰OC(O)NH—;-   R⁹ is independently selected from:    -   a) hydrogen,    -   b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl,        Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰        ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,        and    -   c) C₁-C₆ alkyl unsubstituted or substituted by C₁-C₆        perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—,        (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or        R¹¹OC(O)NR¹⁰—;-   R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl,    2,2,2-trifluoroethyl, benzyl and aryl;-   R¹¹ is independently selected from C₁-C₆ alkyl and aryl;-   R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆    aralkyl, C₁-C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁-C₆    substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,    substituted heteraryl, C₁-C₆ perfluoroalkyl, 2-aminoethyl and    2,2,2-trifluoroethyl;-   A¹ and A² are independently selected from: a bond, —CH═CH—, —C≡C—,    —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹¹)—,    —N(R¹⁰)S(O)₂— or S(O)_(m);-   V is selected from:    -   a) hydrogen,    -   b) heterocycle,    -   c) aryl,    -   d) C₁-C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced        with a heteroatom selected from O, S, and N, and    -   e) C₂-C₂₀ alkenyl,        provided that V is not hydrogen if A¹ is S(O)_(m) and V is not        hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m);-   W is a heterocycle;-   X is a bond, —CH═CH—, O, —C(═O)—, —C(O)NR⁷—, —NR⁷C(O)—, —C(O)O—,    —OC(O)—, —C(O)NR⁷C(O)—, —NR⁷—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂— or    —S(═O)_(m)—;-   m is 0, 1 or 2;-   n is independently 0, 1, 2, 3 or 4;-   p is independently 0, 1, 2, 3 or 4;-   q is 0, 1, 2 or 3;-   r is 0 to 5, provided that r is 0 when V is hydrogen; and-   t is 0 or 1;

(c) a compound represented by formula (II-e):

wherein:

-   R^(1a), R^(1b), R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, A¹, A², V, W,    m, n, p, q, r and t are as previously defined with respect to    formula (II-d);-   from 1-3 of f(s) are independently N, and the remaining f's are    independently CR⁶; and-   each R⁶ is independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹C(O)O—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted C₁-C₆ alkyl,    -   d) substituted C₁-C₆ alkyl wherein the substituent on the        substituted C₁-C₆ alkyl is selected from unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; or    -   any two of R⁶ on adjacent carbon atoms are combined to form a        diradical selected from —CH═CH—CH═CH—, —CH═CH—CH₂—, —(CH₂)₄— and        —(CH₂)₃—;

(d) a compound represented by formula (II-f):

wherein:

-   R³, R⁴, R⁵, R^(6a-e), R⁷, R⁸, R⁹, R¹⁰, R¹¹, A¹, A², V, W, m, n, p,    q, r and t are as previously defined with respect to formula (II-d);-   from 1-2 of f(s) are independently N, and the remaining f's are    independently CH; and-   R¹ and R² are independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, R¹¹C(O)O—,        (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂,        or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted or substituted C₁-C₆ alkyl wherein the        substituent on the substituted C₁-C₆ alkyl is selected from        unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃,        —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;

(f) a compound represented by formula (II-g):

wherein:

-   R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, A¹, A², V, W, m, n, p, q, r and t    are as previously defined with respect to formula (II-d);-   from 1-2 of f(s) are independently N, and the remaining f's are    independently CH;-   from 1-3 of g(s) are independently N, and the remaining g's are    independently CR⁶;-   R¹ and R² are independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, R¹¹C(O)O—,        (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂,        or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted or substituted C₁-C₆ alkyl wherein the        substituent on the substituted C₁-C₆ alkyl is selected from        unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—CNR¹⁰)—, CN, R¹⁰C(O)—, N₃,        —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; and-   each R⁶ is independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹C(O)O—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,-   c) unsubstituted C₁-C₆ alkyl,-   d) substituted C₁-C₆ alkyl wherein the substituent on the    substituted C₁-C₆ alkyl is selected from unsubstituted or    substituted aryl, unsubstituted or substituted heterocyclic, C₃-C₁₀    cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—, R¹¹S(O)_(m)—,    R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—CNR¹⁰)—, CN, R¹⁰C(O)—, N₃,    —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; or    -   any two of R⁶ on adjacent carbon atoms are combined to form a        diradical selected from —CH═CH—CH═CH—, —CH═CH—CH₂—, —(CH₂)₄— and        —(CH₂)₃—;

(g) a compound represented by formula (II-h):

wherein

-   -   R^(C) is selected from:    -   R¹ is hydrogen, an alkyl group, an aralkyl group, an acyl group,        an aracyl group, an aroyl group, an alkylsulfonyl group,        aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and        acyl groups comprise straight chain or branched chain        hydrocarbons of 1 to 6 carbon atoms;    -   R² and R³ are the side chains of naturally occurring amino        acids, including their oxidized forms which may be methionine        sulfoxide or methionine sulfone, or in the alternative may be        substituted or unsubstituted aliphatic, aromatic or        heteroaromatic groups, such as allyl, cyclohexyl, phenyl,        pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms        which may be branched or unbranched, wherein the aliphatic        substitutents may be substituted with an aromatic or        heteroaromatic ring;    -   R⁴ is hydrogen or an alkyl group, wherein the alkyl group        comprises straight chain or branched chain hydrocarbons of 1 to        6 carbon atoms;    -   R⁵ is selected from:        -   a) a side chain of naturally occurring amino acids,        -   b) an oxidized form of a side chain of naturally occurring            amino acids selected from methionine sulfoxide and            methionine sulfone,        -   c) substituted or unsubstituted aliphatic, aromatic or            heteroaromatic groups, such as allyl, cyclohexyl, phenyl,            pyridyl, imidazolyl, or saturated chains of 2 to 8 carbon            atoms which may be branched or unbranched, wherein the            aliphatic substituent is optionally substituted with an            aromatic or heteroaromatic ring, and        -   d) —CH₂CH₂OH or —CH₂CH₂CH₂OH;    -   R⁶ is a substituted or unsubstituted aliphatic, aromatic or        heteroaromatic group such as saturated chains of 1 to 8 carbon        atoms, which may be branched or unbranched, wherein the        aliphatic substituent may be substituted with an aromatic or        heteroaromatic ring;

-   T is O or S(O)_(m);

-   m is 0, 1 or 2;

-   n is 0, 1 or 2;

(h) a compound represented by formula (II-i):

wherein:

-   R^(1a) and R^(1b) are independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, unsubstituted or substituted C₃-C₆        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R⁸O—, R⁹S(O)_(m)—,        R⁸C(O)NR⁸—, CN, NO₂, (R⁸)₂N—C(NR⁸)—, R⁸C(O)—, R⁸OC(O)—, N₃,        —N(R⁸)₂, or R⁹OC(O)NR⁸—,    -   c) C₁-C₆ alkyl unsubstituted or substituted by unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        unsubstituted or substituted C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN,        (R⁸)₂N—C(NR⁸)—, R⁸C(O)—, R⁸OC(O)—, N₃, —N(R⁸)₂, or R⁹OC(O)—NR⁸—;-   R^(2a), R^(2b) and R³ are independently selected from:    -   a) hydrogen,    -   b) C₁-C₆ alkyl unsubstituted or substituted by C₂-C₆ alkenyl,        R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN, N₃, (R⁸)₂N—C(NR⁸), R⁸C(O)—,        R⁸OC(O)—, —N(R⁸)₂, or R⁹OC(O)NR⁸—,    -   c) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, unsubstituted or substituted        cycloalkyl, alkenyl, R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN, NO₂,        (R⁸)₂N—C(NR⁸)—, R⁸C(O)—, R⁸OC(O)—, N₃, —N(R⁸)₂, halogen or        R⁹OC(O)NR⁸—, and    -   d) C₁-C₆ alkyl substituted with an unsubstituted or substituted        group selected from aryl, heterocyclic and C₃-C₁₀ cycloalkyl;-   R⁴ and R⁵ are independently selected from:    -   a) hydrogen, and-   R⁶ is independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, unsubstituted or substituted C₃-C₆        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl,        F, Cl, Br, R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN, NO₂, R⁸        ₂N—C(NR⁸)—, R⁸C(O)—, R⁸OC(O)—, N₃, —N(R⁸)₂, or R⁹OC(O)NR⁸—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by unsubstituted or        substituted aryl, unsubstituted or substituted heterocycle,        unsubstituted or substituted C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R⁸O—,        R⁹S(O)_(m)—, R⁸C(O)NH—, CN, H₂N—C(NH)—, R⁸C(O), R⁸OC(O)—, N₃,        —N(R⁸)₂, or R⁸OC(O)NH—;-   R⁷ is selected from:    -   a) hydrogen,    -   b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl,        Br, R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN, NO₂, (R⁸)₂N—C—(NR⁸)—,        R⁸C(O)—, R⁸OC(O)—, N₃, —N(R⁸)₂, or R⁹OC(O)NR⁸—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by C₁-C₆        perfluoroalkyl, F, Cl, Br, R⁸O—, R⁹S(O)_(m)—, R⁸C(O)NR⁸—, CN,        (R⁸)₂N—C(NR⁸)—, R⁸C(O)—, R⁸OC(O)—, N₃, —N(R⁸)₂, or R⁹OC(O)NR⁸—;-   R⁸ is independently selected from hydrogen, C₁-C₆ alkyl, substituted    or unsubstituted C₁-C₆ aralkyl and substituted or unsubstituted    aryl;-   R⁹ is independently selected from C₁-C₆ alkyl and aryl;-   R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl,    substituted or unsubstituted C₁-C₆ aralkyl and substituted or    unsubstituted aryl;-   A¹ and A² are independently selected from: a bond, —CH═CH—, —C≡C—,    —C(O)—, —C(O)NR⁸—, —NR⁸C(O)—, O, —N(R⁸)—, —S(O)₂N(R⁸)—,    —N(R⁸)S(O)₂—, or S(O)_(m);-   V is selected from:    -   a) hydrogen,    -   b) heterocycle,    -   c) aryl,    -   d) C₁-C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced        with a a heteroatom selected from O, S, and N, and    -   e) C₂-C₂₀ alkenyl,        provided that V is not hydrogen if A¹ is S(O)_(m) and V is not        hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m);-   W is a heterocycle;-   Y is selected from: a bond, —C(R¹⁰)═C(R¹⁰)—, —C≡C—, —C(O)—,    —C(R¹⁰)₂—, —C(OR¹⁰)R¹⁰—, —CN(R¹⁰)₂R¹⁰—, —OC(R¹⁰)₂—, —NR¹⁰C(R¹⁰)₂—,    —C(R¹⁰)₂O—, —C(R¹⁰)₂NR¹⁰—, —C(O)NR¹⁰, —NR¹⁰C(O)—, O, —NC(O)R¹⁰—,    —NC(O)OR¹⁰—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, or S(O)_(m);-   Z is H₂ or O;-   m is 0, 1 or 2;-   n is 0, 1, 2, 3 or 4;-   p is 0, 1, 2, 3 or 4;-   r is 0 to 5, provided that r is 0 when V is hydrogen; and-   u is 0 or 1;

(e) a compound represented by formula (II-m):

wherein:

-   Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a    nitrogen atom through which Q is attached to Y and 0-2 additional    heteroatoms selected from N, S and O, and which also comprises a    carbonyl, thiocarbonyl, —C(═NR¹³)— or sulfonyl moiety adjacent to    the nitrogen atom attached to Y;-   Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3    carbon atoms are replaced by a heteroatom selected from N, S and O,    and wherein Y is attached to Q through a carbon atom;-   R¹ and R² are independently selected from:    -   a) hydrogen,    -   b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, R¹¹C(O)O—,        (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂,        or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted or substituted C₁-C₆ alkyl wherein the        substituent on the substituted C₁-C₆ alkyl is selected from        unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀        cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ²N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃,        —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;-   R³, R⁴ and R⁵ are independently selected from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹C(O)O—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted C₁-C₆ alkyl,    -   d) substituted C₁-C₆ alkyl wherein the substituent on the        substituted C₁-C₆ alkyl is selected from unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,        R¹⁰C(O)—, N₃, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;-   R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) are independently selected    from:    -   a) hydrogen,    -   b) unsubstituted or substituted aryl, unsubstituted or        substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, halogen, C₁-C₆ perfluoroalkyl, R¹²O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹S(O)₂NR¹⁰—, (R¹⁰)₂NS(O)₂—,        R¹¹C(O)O—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or        R¹¹OC(O)NR¹⁰—,    -   c) unsubstituted C₁-C₆ alkyl,    -   d) substituted C₁-C₆ alkyl wherein the substituent on the        substituted C₁-C₆ alkyl is selected from unsubstituted or        substituted aryl, unsubstituted or substituted heterocyclic,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹²O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹S(O)₂NR¹⁰—,        (R¹⁰)₂NS(O)₂—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, and        R¹¹OC(O)—NR¹⁰—; or-   any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacent    carbon atoms are combined to form a diradical selected from    —CH═CH—CH═CH—, —CH═CH—CH₂—, —(CH₂)₄— and —(CH₂)₃—;-   R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle,    aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,    unsubstituted or substituted with:    -   a) C₁₋₄ alkoxy,    -   b) aryl or heterocycle,    -   d) —SO₂R¹¹    -   e) N(R¹⁰)₂ or    -   f) C₁₋₄ perfluoroalkyl;-   R⁸ is independently selected from:    -   a) hydrogen,    -   b) aryl, substituted aryl, heterocycle, substituted heterocycle,        C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl,        F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—,        R¹¹S(O)₂NR¹⁰—, (R¹⁰)₂NS(O)₂—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,        R¹⁰OC(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by aryl,        cyanophenyl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—,        R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹¹S(O)₂NR¹⁰—, (R¹⁰)₂NS(O)₂—, R¹⁰        ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹⁰OC(O)NH—;-   R⁹ is independently selected from:    -   a) hydrogen,    -   b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—,        R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,        NO₂, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and    -   c) C₁-C₆ alkyl unsubstituted or substituted by perfluoroalkyl,        F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰        ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, N₃, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;-   R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl,    2,2,2-trifluoroethyl and aryl;-   R¹¹ is independently selected from C₁-C₆ alkyl and aryl;-   R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆    aralkyl, C₁-C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁-C₆    substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,    substituted heteraryl, C₁-C₆ perfluoroalkyl, 2-aminoethyl and    2,2,2-trifluoroethyl;-   R¹³ is selected from hydrogen, C₁-C₆ alkyl, cyano, C₁-C₆    alkylsulfonyl and C₁-C₆ acyl;-   A¹ and A² are independently selected from: a bond, —CH═CH—, —C≡C—,    —C(O)—, —C(O)NR¹⁰, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,    —N(R¹⁰)S(O)₂—, or S(O)_(m);-   V is selected from:    -   a) hydrogen,    -   b) heterocycle,    -   c) aryl,    -   d) C₁-C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced        with a heteroatom selected from O, S, and N, and    -   e) C₂-C₂₀ alkenyl,        provided that V is not hydrogen if A¹ is S(O)_(m) and V is not        hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m);-   W is a heterocycle;-   X is a bond, —CH═CH—, O, —C(═O)—, —C(O)NR⁷—, —NR⁷C(O)—, —C(O)O—,    —OC(O)—, —C(O)NR⁷C(O)—, —NR⁷—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂— or    —S(═O)_(m)—;-   m is 0, 1 or 2;-   n is independently 0, 1, 2, 3 or 4;-   p is independently 0, 1, 2, 3 or 4;-   q is 0, 1, 2 or 3;-   r is 0 to 5, provided that r is 0 when V is hydrogen; and-   t is 0 or 1;

(f) a compound represented by formula (II-n):

wherein:

-   R¹, R², R³, R⁴, R⁵, R^(6a-e), R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, A¹,    A², V, W, m, n, p, q, r and t are as previously defined with respect    to formula (II-m);-   Q is a 4, 5, 6 or 7 membered heterocyclic ring which comprises a    nitrogen atom through which Q is attached to Y and 0-2 additional    heteroatoms selected from N, S and O, and which also comprises a    carbonyl, thiocarbonyl, —C(═NR¹³)— or sulfonyl moiety adjacent to    the nitrogen atom attached to Y, provided that Q is not-   Y is a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3    carbon atoms are replaced by a heteroatom selected from N, S and O,    and wherein Y is attached to Q through a carbon atom;    or a pharmaceutically acceptable salt or disulfide thereof.

Examples of compounds which selectively inhibit farnesyl proteintransferase include the following:

-   2(S)-Butyl-1-(2,3-diaminoprop-1-yl)-1-(1-naphthoyl)piperazine;-   1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol}methyl-4-(1-naphthoyl)piperazine;-   1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-{5-[1-(4-nitrobenzyl)]imidazolylmethyl}-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-(3-Acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine;-   2(R)-Butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl)piperazine;-   1-2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-naphthoyl)piperazine;-   1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine;-   2(S)-Benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;-   1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl]-4-(1-naphthoyl)piperazine;-   2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine;-   1-(2(R)-Amino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;-   1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine;-   2(S)-n-Butyl-4-(2,3-dimethylphenyl)-1-(4-imidazolylmethyl)-piperazin-5-one;-   2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one;-   1-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one;-   2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(1-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;-   2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;-   2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;-   2(S)-n-Butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;-   2(S)-n-Butyl-1-[1-(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;-   2(S)-n-Butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;-   2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;-   1-[1-(4-Bromohenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine;-   2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethylbenzyl)imidazol-5-ylmethyl]-piperazine;-   2(S)-n-Butyl-1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;-   2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;-   1-[1-(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)-piperazine;-   2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)imidazol-5-ylmethyl]-piperazine;-   2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy)imidazol-5-ylmethyl]piperazine;-   1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine;-   (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinone;-   (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone;-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;-   (S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetamido]-2-piperazinone;-   (±)-5-(2-Butynyl)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;-   5(S)-Butyl-4-[1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-1-(2,3-dimethylphenyl)-piperazin-2-one;-   4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one;-   5(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-methylphenyl)piperazin-2-one;-   4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one;-   4-[3-(4-Cyanobenzyl)pyridin-4-yl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one;-   4-[5-(4-Cyanobenzyl)-1-imidazolylethyl]-1-(3-chlorophenyl)piperazin-2-one;-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-4-pentenoyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-4-pentenoyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxypentanoyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3    (S)-methyl]pentyloxypentanoyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3    (S)-methyl]5-pentyloxy-4-methylpentanoyl-homoserine lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-4-methylpentanoyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylbutanoyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylbutanoyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3    (S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine    lactone,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3    (S)-methyl]-pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    methyl ester,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3    (S)-methyl]pentyloxy-3-phenylpropionyl-methionine,-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine    sulfone methyl ester (Compound 5),-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine    sulfone (Compound 6),-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyt-methionine    sulfone methyl ester,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyl-methionine    sulfone,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine    sulfone methyl ester,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methionine    sulfone,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-methionine    methyl ester,-   2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-methionine,-   Disulphide of    2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserine    lactone,-   Disulphide of    2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine,-   Disulphide of    2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-methylbutanoyl-methionine    methyl ester-   1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(4-Cyanobenzyl)-5-(4′-phenylbenzamido)ethyl-imidazole-   1-(2′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4-(3′,5′-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4-(3′,5′-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole-   1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole-   5-(4-Cyanophenyloxy)-1-(2′-methyl-4-biphenylmethyl)-imidazole-   5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole-   5-(2′-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole-   5-(4-(3′,5′-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazole-   1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole-   1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)    methylimidazole-   1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl)    methylimidazole-   1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole-   1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(4-biphenyl)-methyl imidazole-   1-(4-Cyanobenzyl)-5-(1-oxo-1-(4-biphenyl)-methyl imidazole-   1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole-   1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole-   5-(2-[1,1′-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene-   1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole-   1-(3′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(3′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(3′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′3′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′4′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′5′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(3′-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(4-(2′-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-{1-(4-(2′-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)    imidazole-   1-(2′-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole-   1-(2′-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)    imidazole-   1-(2′-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl) imidazole-   1-(2′-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl) imidazole-   1-(3′-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole-   1-(3′-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3′-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)    imidazole-   1-(3′-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3′-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-Chloro-4′-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2′-Ethyl-4-biphenylmethyl)-5-(4-(1H-tetrazol-5-yl))benzyl)imidazole-   1-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2′-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzene-   1-(3′,5′-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3′,5′-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3′,5′-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole-   1-(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(4-Cyanobenzyl)-2-methyl-5-(2′-methylbiphenyl-4-yloxy)imidazole-   5-(4-Cyanobenzyl)-1-(3-cyano-2′-trifluoromethylbiphenyl-4-ylmethyl)-imidazole-   2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole-   2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole-   1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole-   1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole-   1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole-   1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole-   1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole-   1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole-   1-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazole and-   1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole-   1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(4-[3-Methylpyrazin-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(4-(Pyrimidinyl-5-yl)phenylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole-   1-(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole-   N-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-amino-pyrimidine-   N,N-bis(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene-   N,N-bis(4-Imidazolemethyl)amino-4-[(3-carboxyphenyl)oxy]benzene-   N,N-bis(4-Imidazolemethyl)amino-3-[(3-carbomethoxyphenyl)-oxy]benzene-   N,N-bis(4-Imidazolemethyl)amino-4-[(3-carbomethoxyphenyl)-oxy]benzene-   N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3-carboxyphenyl)oxy]benzene-   N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3-carbomethoxyphenyl)oxy]benzene-   N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene-   N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzene-   N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenylthio)benzene-   N-Butyl-N-[1-(4-cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzene-   N-[1-(4-Cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzene-   N-(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene-   (±)-4-[(4-imidazolylmethyl)amino]pentyl-1-(phenoxy)benzene-   1-[(N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino)methyl]-4-(phenoxy)benzene-   4-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino]-1-(phenylthio)benzene-   (±)-4-[N-(1-(4-cyanobenzyl)-4-imidazolylmethyl)-N-(n-butyl)amino]-1-(phenylsulfinyl)benzene-   3-[N-(4-imidazolylmethyl)-N-(n-butyl)amino]-N-(phenyl)benzenesulfonamide    and-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene-   4-{3-[4-(-2-Oxo-2-H-pyridin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile-   4-{3-[4-3-Methyl-2-oxo-2-H-pyridin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile-   4-{3-[4-(-2-Oxo-piperidin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile-   4-{3-[3-Methyl-4-(2-oxopiperidin-1-yl)-benzyl]-3-H-imidizol-4-ylmethyl}-benzonitrile-   (4-{3-[4-(2-Oxo-pyrrolidin-1-yl)-benzyl]-3H-imidizol-4-ylmethyl}-benzonitrile-   4-{3-[4-(3-Methyl-2-oxo-2-H-pyrazin-1-yl)-benzyl-3-H-imidizol-4-ylmethyl}-benzonitrile-   4-{3-[2-Methoxy-4-(2-oxo-2-H-pyridin-1-yl)-benzyl]-3-H-imidizol-4-ylmethyl}-benzonitrile-   4-{1-[4-(5-Chloro-2-oxo-2H-pyridin-1-yl)-benzyl]-1H-pyrrol-2-ylmethyl}-benzonitrile-   4-[1-(2-Oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile-   4-[3-(2-Oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile-   4-{3-[1-(3-Chloro-phenyl)-2-oxo-1,2-dihydropyridin-4-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile    or a pharmaceutically acceptable salt, disulfide or optical isomer    thereof.

Specific examples of a farnesyl-protein transferase inhibitor is

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A)-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile    and-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt, disulfide or optical isomer    thereof.

A particularly useful example of the instant method comprisesadministering an effective amount of a combination of paclitaxel and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of vinblastine and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of 5-fluorouracil anda farnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of colchicine and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of estramustine and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of etoposide and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of doxorubicin and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of cis-platinum and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of bicalutamide and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone A and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone B and afarnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Aand a farnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Band a farnesyl-protein transferase inhibitor which is:

-   2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine    sulfone isopropyl ester (Compound A).

A particularly useful example of the instant method comprisesadministering an effective amount of a combination of paclitaxel and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of vinblastine and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of 5-fluorouracil anda farnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of colchicine and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of estramustine and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of etoposide and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of doxorubicin and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of cis-platinum and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of bicalutamide and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone A and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone B and afarnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Aand a farnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Band a farnesyl-protein transferase inhibitor which is:

-   1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

A particularly useful example of the instant method comprisesadministering an effective amount of a combination of paclitaxel and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of vinblastine and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of 5-fluorouracil anda farnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of colchicine and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of estramustine and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of etoposide and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of doxorubicin and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of cis-platinum and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of bicalutamide and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone A and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone B and afarnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Aand a farnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Band a farnesyl-protein transferase inhibitor which is:

-   (R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of paclitaxel and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of vinblastine and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of 5-fluorouracil anda farnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of colchicine and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of estramustine and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of etoposide and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of doxorubicin and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of cis-platinum and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5    ′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of bicalutamide and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone A and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5    ′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone B and afarnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Aand a farnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Band a farnesyl-protein transferase inhibitor which is:

-   4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of paclitaxel and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of vinblastine and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of 5-fluorouracil anda farnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of colchicine and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of estramustine and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of etoposide and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of doxorubicin and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of cis-platinum and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of bicalutamide and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone A and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of epothilone B and afarnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Aand a farnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Another particularly useful example of the instant method comprisesadministering an effective amount of a combination of desoxyepothilone Band a farnesyl-protein transferase inhibitor which is:

-   1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene;    or a pharmaceutically acceptable salt thereof.

Compounds which are described as inhibitors of farnesyl-proteintransferase and may therefore useful in the present invention, andmethods of synthesis thereof, can be found in the following patents,pending applications and publications, which are herein incorporated byreference:

-   WO 95/32987 published on 7 Dec. 1995;-   U.S. Pat. No. 5,420,245;-   U.S. Pat. No. 5,523,430;-   U.S. Pat. No. 5,532,359;-   U.S. Pat. No. 5,510,510;-   U.S. Pat. No. 5,589,485;-   U.S. Pat. No. 5,602,098;-   European Pat. Publ. 0 618 221;-   European Pat. Publ. 0 675 112;-   European Pat. Publ. 0 604 181;-   European Pat. Publ. 0 696 593;-   WO 94/19357;-   WO 95/08542;-   WO 95/11917;-   WO 95/12612;-   WO 95/12572;-   WO 95/10514 and U.S. Pat. No. 5,661,152;-   WO 95/10515;-   WO 95/10516;-   WO 95/24612;-   WO 95/34535;-   WO 95/25086;-   WO 96/05529;-   WO 96/06138;-   WO 96/06193;-   WO 96/16443;-   WO 96/21701;-   WO 96/21456;-   WO 96/22278;-   WO 96/24611;-   WO 96/24612;-   WO 96/05168;-   WO 96/05169;-   WO 96/00736 and U.S. Pat. No. 5,571,792 granted on Nov. 5, 1996;-   WO 96/17861;-   WO 96/33159;-   WO 96/34850;-   WO 96/34851;-   WO 96/30017;-   WO 96/30018;-   WO 96/30362;-   WO 96/30363;-   WO 96/31111;-   WO 96/31477;-   WO 96/31478;-   WO 96/31501;-   WO 97/00252;-   WO 97/03047;-   WO 97/03050;-   WO 97/04785;-   WO 97/02920;-   WO 97/17070;-   WO 97/23478;-   WO 97/26246;-   WO 97/30053;-   WO 97/44350;-   WO 98/02436; and-   U.S. Pat. No. 5,532,359 granted on Jul. 2, 1996.

Compounds which are inhibitors of farnesyl-protein transferase and aretherefore useful in the present invention, and methods of synthesisthereof, can be found in the following patents, pending applications andpublications, which are herein incorporated by reference:

-   U.S. Pat. No. 5,238,922 granted on Aug. 24, 1993;-   U.S. Pat. No. 5,340,828 granted on Aug. 23, 1994;-   U.S. Pat. No. 5,480,893 granted on Jan. 2, 1996;-   U.S. Pat. No. 5,352,705 granted on Oct. 4, 1994;-   U.S. Pat. No. 5,504,115 granted on Apr. 2, 1996;-   U.S. Pat. No. 5,536,750 granted on Jul. 16, 1996;-   U.S. Pat. No. 5,504,212 granted on Apr. 2, 1996;-   U.S. Pat. No. 5,439,918 granted on Aug. 8, 1995;-   U.S. Pat. No. 5,686,472 granted on Nov. 11, 1997;-   U.S. Pat. No. 5,736,539 granted on Apr. 4, 1998;-   U.S. Pat. No. 5,576,293 granted on Nov. 19, 1996;-   U.S. Pat. No. 5,468,733 granted on Nov. 21, 1995;-   WO 96/06609 (Mar. 3, 1996) and U.S. Ser. No. 08/298,478 filed on    Aug. 24, 1994;-   U.S. Pat. No. 5,585,359 granted on Dec. 17, 1996-   U.S. Pat. No. 5,523,456 granted on Jun. 4, 1996;-   U.S. Pat. No. 5,661,161 granted on Aug. 26, 1997;-   U.S. Pat. No. 5,571,835 granted on Nov. 5, 1996;-   U.S. Pat. No. 5,491,164 granted on Feb. 13, 1996;-   U.S. Pat. No. 5,652,257 granted on Jul. 29, 1997;-   U.S. Pat. No. 5,631,280 granted on May 20, 1997;-   U.S. Pat. No. 5,578,629 granted on Nov. 26, 1996;-   U.S. Pat. No. 5,627,202 granted on May 6, 1997;-   WO 96/30343 (Oct. 3, 1996); U.S. Ser. No. 08/412,829 filed on Mar.    29, 1995; and U.S. Ser. No. 08/470,690 filed on Jun. 6, 1995; and    U.S. Ser. No. 08/600,728 filed on Feb. 28, 1996;-   U.S. Pat. No. 5,624,936 granted on Apr. 29, 1997;-   U.S. Pat. No. 5,534,537 granted on Jul. 9, 1996;-   U.S. Pat. No. 5,710,171 granted on Apr. 29, 1997;-   WO 96/39137 (Dec. 12, 1996); U.S. Ser. No. 08/468,160 filed on Jun.    6, 1995; U.S. Ser. No. 08/652,055 filed on May 23, 1996; U.S. Ser.    No. 08/960,248 filed Oct. 29, 1997;-   U.S. Pat. No. 5,703,241 granted on Dec. 30, 1997;-   WO 97/18813; U.S. Ser. No. 08/749,254 filed on Nov. 15, 1996;-   WO 97/27854 (Aug. 7, 1997); U.S. Ser. No. 60/010,799 filed on Jan.    30, 1996; U.S. Ser. No. 08/786,520 filed on Jan. 21, 1997; U.S. Ser.    No. 09/015,823 filed on Jan. 29, 1998;-   WO 97/27752 (Aug. 7, 1997); U.S. Ser. No. 60/010,860 filed on Jan.    30, 1996; U.S. Ser. No. 08/784,556 filed on Jan. 21, 1997; U.S. Ser.    No. 09/030,223 filed on Feb. 25, 1998;-   WO 97/27853 (Aug. 7, 1997); U.S. Ser. No. 60/011,081 filed on Jan.    30, 1996; U.S. Ser. No. 08/786,519 filed on Jan. 21, 1997; U.S. Ser.    No. 09/______ filed on Mar. 20, 1998;-   WO 97/27852 (Aug. 7, 1997); U.S. Ser. No. 60/010,798 filed on Jan.    30, 1996; U.S. Ser. No. 08/786,516 filed on Jan. 21, 1997;-   WO 97/36888 (Oct. 9, 1997); U.S. Ser. No. 60/014,587 filed on Apr.    3, 1996; U.S. Ser. No. 08/823,919 filed on Mar. 25, 1997;-   WO 97/36889 (Oct. 9, 1997); U.S. Ser. No. 60/014,589 filed on Apr.    3, 1996; U.S. Ser. No. 08/823,923 filed on Mar. 25, 1997;-   WO 97/36876 (Oct. 9, 1997); U.S. Ser. No. 60/014,592 filed on Apr.    3, 1996; U.S. Ser. No. 08/834,671 filed on Apr. 1, 1997;-   WO 97/36593 (Oct. 9, 1997); U.S. Ser. No. 60/014,593 filed on Apr.    3, 1996; U.S. Ser. No. 08/827,485, filed on Mar. 27, 1997;-   WO 97/36879 (Oct. 9, 1997); U.S. Ser. No. 60/014,594 filed on Apr.    3, 1996; U.S. Ser. No. 08/823,920 filed on Mar. 25, 1997;-   WO 97/36583 (Oct. 9, 1997); U.S. Ser. No. 60/014,668 filed on Apr.    3, 1996; U.S. Ser. No. 08/824,588 filed on Mar. 26, 1997;-   WO 97/36592 (Oct. 9, 1997); U.S. Ser. No. 60/014,775 filed on Apr.    3, 1996; U.S. Ser. No. 08/826,292 filed on Mar. 27, 1997;-   WO 97/36584 (Oct. 9, 1997); U.S. Ser. No. 60/014,776 filed on Apr.    3, 1996; U.S. Ser. No. 08/824,427 filed on Mar. 26, 1997;-   U.S. Ser. No. 60/014,777 filed on Apr. 3, 1996; U.S. Ser. No.    08/826,317 filed on Mar. 27, 1997;-   WO 97/38665 (Oct. 23, 1997); U.S. Ser. No. 60/014,791 filed on Apr.    3, 1996; U.S. Ser. No. 08/831,308 filed on Apr. 1, 1997;-   WO 97/36591 (Oct. 9, 1997); U.S. Ser. No. 60/014,792 filed on Apr.    3, 1996; U.S. Ser. No. 08/827,482, filed on Mar. 27, 1997;-   WO 97/36605 (Oct. 9, 1997); U.S. Ser. No. 60/014,793 filed on Apr.    3, 1996; U.S. Ser. No. 08/823,934 filed on Mar. 25, 1997;-   WO 97/37877 (Oct. 9, 1997); U.S. Ser. No. 60/014,794 filed on Apr.    3, 1996; U.S. Ser. No. 08/834,675 filed on Apr. 1, 1997;-   WO 97/37900 (Oct. 9, 1997); U.S. Ser. No. 60/014,798 filed on Apr.    3, 1996; U.S. Ser. No. 08/823,929 filed on Mar. 25, 1997;-   WO 97/36891 (Oct. 9, 1997); U.S. Ser. No. 60/014,774 filed on Apr.    3, 1996; U.S. Ser. No. 08/826,291 filed on Mar. 27, 1997;-   WO 97/36886 (Oct. 9, 1997); U.S. Ser. No. 60/022,332 filed on Jul.    24, 1996; U.S. Ser. No. 08/823,919, filed on Mar. 27, 1997;-   WO 97/36881 (Oct. 9, 1997); U.S. Ser. No. 60/022,340 filed on Jul.    24, 1996; U.S. Ser. No. 08/827,486, filed on Mar. 27, 1997;-   WO 97/36585 (Oct. 9, 1997); U.S. Ser. No. 60/022,341 filed on Jul.    24, 1996; U.S. Ser. No. 08/826,251 filed on Mar. 27, 1997;-   WO 97/36898 (Oct. 9, 1997); U.S. Ser. No. 60/022,342 filed on Jul.    24, 1996; U.S. Ser. No. 08/825,293 filed on Mar. 27, 1997;-   WO 97/36897 (Oct. 9, 1997); U.S. Ser. No. 60/022,558 filed on Jul.    24, 1996; U.S. Ser. No. 08/827,476, filed on Mar. 27, 1997;-   WO 97/36874 (Oct. 9, 1997);-   WO 97/36585 (Oct. 9, 1997); U.S. Ser. No. 60/022,586 filed on Jul.    24, 1996; U.S. Ser. No. 08/827,484, filed on Mar. 27, 1997;-   WO 97/36890 (Oct. 9, 1997); U.S. Ser. No. 60/022,587 filed on Jul.    24, 1996; U.S. Ser. No. 08/831,105 filed on Apr. 1, 1997;-   WO 97/36901 (Oct. 9, 1997); U.S. Ser. No. 60/022,647 filed on Jul.    24, 1996; U.S. Ser. No. 08/827,483, filed on Mar. 27, 1997;-   U.S. Ser. No. 60/032,126 filed on Dec. 5, 1996; U.S. Ser. No.    08/985,732, filed on Dec. 4, 1997;-   U.S. Ser. No. 60/032,428 filed on Dec. 5, 1996; U.S. Ser. No.    08/985,124, filed on Dec. 4, 1997;-   U.S. Ser. No. 60/032,578 filed on Dec. 5, 1996; U.S. Ser. No.    08/985,337, filed on Dec. 4, 1997;-   U.S. Ser. No. 60/032,579 filed on Dec. 5, 1996; U.S. Ser. No.    08/985,320, filed on Dec. 5, 1997;-   U.S. Ser. No. 60/033,990, filed on Dec. 30, 1996; U.S. Ser. No.    08/995,744, filed on Dec. 22, 1997; and-   U.S. Ser. No. 60/033,991, filed on Dec. 30, 1996; U.S. Ser. No.    08/985,124, filed on Dec. 5, 1997.    All patents, publications and pending patent applications identified    are hereby incorporated by reference.

With respect to the compounds of formulas II-a through II-n thefollowing definitions apply:

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 15 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred straight or branchedalkyl groups include methyl, ethyl, propyl, isopropyl, butyl andt-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.

When substituted alkyl is present, this refers to a straight, branchedor cyclic alkyl group as defined above, substituted with 1-3 groups asdefined with respect to each variable.

Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, andinterrupted by from 1-4 heteroatoms selected from O, S and N.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 15 carbon atoms and at least one carbon tocarbon double bond. Preferably one carbon to carbon double bond ispresent, and up to four non-aromatic (non-resonating) carbon-carbondouble bonds may be present. Examples of alkenyl groups include vinyl,allyl, iso-propenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and thelike. Preferred alkenyl groups include ethenyl, propenyl, butenyl andcyclohexenyl. As described above with respect to alkyl, the straight,branched or cyclic portion of the alkenyl group may contain double bondsand may be substituted when a substituted alkenyl group is provided.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 15 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Preferred alkynyl groups include ethynyl, propynyl and butynyl.As described above with respect to alkyl, the straight, branched orcyclic portion of the alkynyl group may contain triple bonds and may besubstituted when a substituted alkynyl group is provided.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and likegroups as well as rings which are fused, e.g., naphthyl and the like.Aryl thus contains at least one ring having at least 6 atoms, with up totwo such rings being present, containing up to 10 atoms therein, withalternating (resonating) double bonds between adjacent carbon atoms. Thepreferred aryl groups are phenyl and naphthyl. Aryl groups may likewisebe substituted as defined below. Preferred substituted aryls includephenyl and naphthyl substituted with one or two groups. With regard tothe farnesyl transferase inhibitors, “aryl” is intended to include anystable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7members in each ring, wherein at least one ring is aromatic. Examples ofaryl groups include phenyl, naphthyl, anthracenyl, biphenyl,tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S or N, in which a carbonor nitrogen atom is the point of attachment, and in which one additionalcarbon atom is optionally replaced by a heteroatom selected from O or S,and in which from 1 to 3 additional carbon atoms are optionally replacedby nitrogen heteroatoms. The heteroaryl group is optionally substitutedwith up to three groups.

Heteroaryl thus includes aromatic and partially aromatic groups whichcontain one or more heteroatoms. Examples of this type are thiophene,purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole,tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.Examples of partially aromatic groups aretetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as definedbelow.

With regard to the farnesyl transferase inhibitors, the term heterocycleor heterocyclic, as used herein, represents a stable 5- to 7-memberedmonocyclic or stable 8- to 11-membered bicyclic or stable 11-15 memberedtricyclic heterocycle ring which is either saturated or unsaturated, andwhich consists of carbon atoms and from one to four heteroatoms selectedfrom the group consisting of N, O, and S, and including any bicyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached at any heteroatom orcarbon atom which results in the creation of a stable structure.Examples of such heterocyclic elements include, but are not limited to,azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.Preferably, heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl,piperidyl, pyridyl and pyrrolidinyl.

With regard to the farnesyl transferase inhibitors, the terms“substituted aryl”, “substituted heterocycle” and “substitutedcycloalkyl” are intended to include the cyclic group which issubstituted with 1 or 2 substitutents selected from the group whichincludes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁-C₆ alkyl)₂,NO₂, CN, (C₁-C₆ alkyl)O—, —OH, (C₁-C₆ alkyl)S(O)_(m)—, (C₁-C₆alkyl)C(O)NH—, H₂N—C(NH)—, (C₁-C₆ alkyl)C(O)—, (C₁-C₆ alkyl)OC(O)—, N₃,(C₁-C₆ alkyl)OC(O)NH— and C₁-C₂₀ alkyl.

In the present method, amino acids which are disclosed are identifiedboth by conventional 3 letter and single letter abbreviations asindicated below: Alanine Ala A Arginine Arg R Asparagine Asn N Asparticacid Asp D Asparagine or Asx B Aspartic acid Cysteine Cys C GlutamineGln Q Glutamic acid Glu E Glutamine or Glx Z Glutamic acid Glycine Gly GHistidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K MethionineMet M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr TTryptophan Trp W Tyrosine Tyr Y Valine Val V

The compounds used in the present method may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. Unless otherwise specified, named amino acids areunderstood to have the natural “L” stereoconfiguration.

With respect to the farnesyl-protein transferase inhibitors of theformulas II-d and II-f, the substituent illustrated by the structure

is a simplified representation of a phenyl ring having five (5)substituents (hydrogens and/or non-hydrogens) and may also berepresented by the structure:

With respect to the farnesyl-protein transferase inhibitors of theformulas II-d and II-f, the moiety described as

where any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacentcarbon atoms are combined to form a diradical selected from—CH═CH—CH═CH, —CH═CH—CH—, —(CH₂)₄— and —(CH₂)₄— includes the followingstructures:

It is understood that such fused ring moieties may be furthersubstituted by the remaining R^(6a), R^(6b), R^(6c), R^(6d) and/orR^(6e) as defined hereinabove.

With respect to the farnesyl-protein transferase inhibitors of theformulas II-e and II-g, the moieties designated by the followingstructures:

represent an aromatic 6-membered heterocyclic ring and includes thefollowing ring systems:

wherein R⁶ is as defined hereinabove.

With respect to the farnesyl-protein transferase inhibitors of theformulas II-e and II-g, the moieties designated by the followingstructures:

where any two of R⁶ on adjacent carbon atoms are combined to form adiradical selected from —CH═CH—CH═CH—, —CH═CH—CH—, —(CH₂)₄— and —(CH₂)₄—include, but are not limited to the following structures:

It is understood that such fused ring moieties may be furthersubstituted by the remaining R⁶s as defined hereinabove.

With respect to the farnesyl-protein transferase inhibitors of theformulas II-f and II-g, the moiety designated by the followingstructure:

represents an aromatic 6-membered heterocyclic ring and includes thefollowing ring systems:

wherein it is understood that one of the ring carbon atoms issubstituted with

respectively.

With respect to the farnesyl-protein transferase inhibitors of theformula II-m, the substituent illustrated by the structure:

represents a 4, 5, 6 or 7 membered heterocyclic ring which comprises anitrogen atom through which Q is attached to Y and 0-2 additionalheteroatoms selected from N, S and O, and which also comprises acarbonyl, thiocarbonyl, —C(═NR¹³)— or sulfonyl moiety adjacent to thenitrogen atom attached to Y and includes the following ring systems:

It is understood that such rings may be substituted by R^(6a), R^(6b),R^(6c), R^(6d) and/or R^(6e) as defined hereinabove.

With respect to the farnesyl-protein transferase inhibitors of theformula II-m, the moiety described as

where any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacentcarbon atoms are combined to form a diradical selected from—CH═CH—CH═CH, —CH═CH—CH—, —(CH₂)₄— and —(CH₂)₄— includes, but is notlimited to, the following structures:

It is understood that such fused ring moieties may be furthersubstituted by the remaining R^(6a), R^(6b), R^(6c), R^(6d) and/orR^(6e) as defined hereinabove.

With respect to the farnesyl-protein transferase inhibitors of theformula II-m, the substituent illustrated by the structure:

represents a 5, 6 or 7 membered carbocyclic ring wherein from 0 to 3carbon atoms are replaced by a heteroatom selected from N, S and O, andwherein Y is attached to Q through a carbon atom and includes thefollowing ring systems:

With respect to the farnesyl-protein transferase inhibitors of theformula II-n, the substituent illustrated by the structure:

represents a 4, 5, 6 or 7 membered heterocyclic ring which comprises anitrogen atom through which Q is attached to Y and 0-2 additionalheteroatoms selected from N, S and O, and which also comprises acarbonyl, thiocarbonyl, —C(═NR¹³)— or sulfonyl moiety adjacent to thenitrogen atom attached to Y and includes the following ring systems:

With respect to the farnesyl-protein transferase inhibitors of theformula II-n, the substituent illustrated by the structure:

represents a 5-, 6- or 7-membered carbocyclic ring wherein from 0 to 3carbon atoms are replaced by a heteroatom selected from N, S and O, andwherein Y is attached to Q through a carbon atom and includes thefollowing ring systems:

With respect to the farnesyl-protein transferase inhibitors of theformula II-n, the moiety described as

where any two of R^(6a), R^(6b), R^(6c), R^(6d) and R^(6e) on adjacentcarbon atoms are combined to form a diradical selected from—CH═CH—CH═CH, —CH═CH—CH—, —(CH₂)₄— and —(CH₂)₄— includes, but is notlimited to, the following structures:

It is understood that such fused ring moieties may be furthersubstituted by the remaining R^(6a), R^(6b), R^(6c), R^(6d) and/orR^(6e) as defined hereinabove.

When R² and R³ are combined to form —(CH₂)_(u)—, cyclic moieties areformed. Examples of such cyclic moieties include, but are not limitedto:

In addition, such cyclic moieties may optionally include aheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to:

When R⁶ and R⁷, R⁷ and R^(7a), or are combined to form —(CH₂)_(u)—,cyclic moieties are formed. Examples of such cyclic moieties include,but are not limited to:

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable (e.g.,R¹⁰, Z, n, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. Thus, —N(R¹⁰)₂ represents—NHH, —NHCH₃, —NHC₂H₅, etc. It is understood that substituents andsubstitution patterns on the compounds of the instant invention can beselected by one of ordinary skill in the art to provide compounds thatare chemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth below.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base with stoichiometric amounts or withan excess of the desired salt-forming inorganic or organic acid in asuitable solvent or various combinations of solvents.

The compounds of formula (II-h) can be synthesized from theirconstituent amino acids by conventional peptide synthesis techniques,and the additional methods described below. Standard methods of peptidesynthesis are disclosed, for example, in the following works: Schroederet al., “The Peptides”, Vol. I, Academic Press 1965, or Bodanszky etal., “Peptide Synthesis”, Interscience Publishers, 1966, or McOmie (ed.)“Protective Groups in Organic Chemistry”, Plenum Press, 1973, or Baranyet al., “The Peptides: Analysis, Synthesis, Biology” 2, Chapter 1,Academic Press, 1980, or Stewart et al., “Solid Phase PeptideSynthesis”, Second Edition, Pierce Chemical Company, 1984. Also usefulin exemplifying syntheses of specific unnatural amino acid residues areEuropean Pat. Appl. No. 0 350 163 A2 (particularly page 51-52) and J. E.Baldwin et al. Tetrahedron, 50:5049-5066 (1994). With regards to thesynthesis of instant compounds containing a (β-acetylamino)alanineresidue at the C-terminus, use of the commercially availableN_(α)-Z-L-2,3-diaminopropionic acid (Fluka) as a starting material ispreferred.

Abbreviations used in the description of the chemistry and in theExamples that follow are: Ac₂O Acetic anhydride; Boc t-Butoxycarbonyl;DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP 4-Dimethylaminopyridine;DME 1,2-Dimethoxyethane; DMF Dimethylformamide; EDC1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide- hydrochloride; HOBT1-Hydroxybenzotriazole hydrate; Et₃N Triethylamine; EtOAc Ethyl acetate;FAB Fast atom bombardment; HOOBT 3-Hydroxy-1,2,2-benzotriazin-4(3H)-one;HPLC High-performance liquid chromatography; MCPBA m-Chloroperoxybenzoicacid; MsCl Methanesulfonyl chloride; NaHMDS Sodiumbis(trimethylsilyl)amide; Py Pyridine; TFA Trifluoroacetic acid; THFTetrahydrofuran.

The compounds are useful in various pharmaceutically acceptable saltforms. The term “pharmaceutically acceptable salt” refers to those saltforms which would be apparent to the pharmaceutical chemist. i.e., thosewhich are substantially non-toxic and which provide the desiredpharmacokinetic properties, palatability, absorption, distribution,metabolism or excretion. Other factors, more practical in nature, whichare also important in the selection, are cost of the raw materials, easeof crystallization, yield, stability, hygroscopicity and flowability ofthe resulting bulk drug. Conveniently, pharmaceutical compositions maybe prepared from the active ingredients in combination withpharmaceutically acceptable carriers.

Pharmaceutically acceptable salts include conventional non-toxic saltsor quaternary ammonium salts formed, e.g., from non-toxic inorganic ororganic acids. Non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base, in a suitable solvent or solvent combination.

The farnesyl transferase inhibitors of formula (II-a) through (II-c) canbe synthesized in accordance with Schemes 1-22, in addition to otherstandard manipulations such as ester hydrolysis, cleavage of protectinggroups, etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R, R^(a) and R^(b), as shown inthe Schemes, represent the substituents R², R³, R⁴, and R⁵; howevertheir point of attachment to the ring is illustrative only and is notmeant to be limiting.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes.

Synopsis of Schemes 1-22:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.In Scheme 1, for example, the synthesis of 2-alkyl substitutedpiperazines is outlined, and is essentially that described by J. S.Kiely and S. R. Priebe in Organic Preparations and Proceedings Int.,1990, 22, 761-768. Boc-protected amino acids I, available commerciallyor by procedures known to those skilled in the art, can be coupled toN-benzyl amino acid esters using a variety of dehydrating agents such asDCC (dicyclohexycarbodiimide) or EDC.HCl(1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride) in asolvent such as methylene chloride , chloroform, dichloroethane, or indimethylformamide. The product II is then deprotected with acid, forexample hydrogen chloride in chloroform or ethyl acetate, ortrifluoroacetic acid in methylene chloride, and cyclized under weaklybasic conditions to give the diketopiperazine III. Reduction of III withlithium aluminum hydride in refluxing ether gives the piperazine IV,which is protected as the Boc derivative V. The N-benzyl group can becleaved under standard conditions of hydrogenation, e.g., 10% palladiumon carbon at 60 psi hydrogen on a Parr apparatus for 24-48 h. Theproduct VI can be treated with an acid chloride, or a carboxylic acidunder standard dehydrating conditions to furnish the carboxamides VII; afinal acid deprotection as previously described gives the intermediateVIII (Scheme 2). The intermediate VIII can be reductively alkylated witha variety of aldehydes, such as IX. The aldehydes can be prepared bystandard procedures, such as that described by O. P. Goel, U. Krolls, M.Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid (Scheme 3). The reductive alkylation can beaccomplished at pH 5-7 with a variety of reducing agents, such as sodiumtriacetoxyborohydride or sodium cyanoborohydride in a solvent such asdichloroethane, methanol or dimethylformamide. The product X can bedeprotected to give the final compounds XI with trifluoroacetic acid inmethylene chloride. The final product XI is isolated in the salt form,for example, as a trifluoroacetate, hydrochloride or acetate salt, amongothers. The product diamine XI can further be selectively protected toobtain XII, which can subsequently be reductively alkylated with asecond aldehyde to obtain XIII. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole XV can beaccomplished by literature procedures.

Alternatively, the protected piperazine intermediate VII can bereductively alkylated with other aldehydes such as1-trityl-4-imidazolyl-carboxaldehyde or1-trityl-4-imidazolylacetaldehyde, to give products such as XVI (Scheme4). The trityl protecting group can be removed from XVI to give XVII, oralternatively, XVI can first be treated with an alkyl halide thensubsequently deprotected to give the alkylated imidazole XVIII.Alternatively, the intermediate VIII can be acylated or sulfonylated bystandard techniques. The imidazole acetic acid XIX can be converted tothe acetate XXI by standard procedures, and XXI can be first reactedwith an alkyl halide, then treated with refluxing methanol to providethe regiospecifically alkylated imidazole acetic acid ester XXII.Hydrolysis and reaction with piperazine VIII in the presence ofcondensing reagents such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylatedproducts such as XXIV.

If the piperazine VIII is reductively alkylated with an aldehyde whichalso has a protected hydroxyl group, such as XXV in Scheme 6, theprotecting groups can be subsequently removed to unmask the hydroxylgroup (Schemes 6, 7). The alcohol can be oxidized under standardconditions to e.g. an aldehyde, which can then be reacted with a varietyof organometallic reagents such as Grignard reagents, to obtainsecondary alcohols such as XXIX. In addition, the fully deprotectedamino alcohol XXX can be reductively alkylated (under conditionsdescribed previously) with a variety of aldehydes to obtain secondaryamines, such as XXXI (Scheme 7), or tertiary amines.

The Boc protected amino alcohol XXVII can also be utilized to synthesize2-aziridinylmethylpiperazines such as XXXII (Scheme 8). Treating XXVIIwith 1,1′-sulfonyldiimidazole and sodium hydride in a solvent such asdimethylformamide led to the formation of aziridine XXXII. The aziridinereacted in the presence of a nucleophile, such as a thiol, in thepresence of base to yield the ring-opened product XXXIII.

In addition, the piperazine VIII can be reacted with aldehydes derivedfrom amino acids such as O-alkylated tyrosines, according to standardprocedures, to obtain compounds such as XXXIX. When R′ is an aryl group,XXXIX can first be hydrogenated to unmask the phenol, and the aminegroup deprotected with acid to produce XL. Alternatively, the amineprotecting group in XXXIX can be removed, and O-alkylated phenolicamines such as XLI produced.

Depending on the identity of the amino acid I, various side chains canbe incorporated into the piperazine. For example when I is theBoc-protected β-benzyl ester of aspartic acid, the intermediatediketopiperazine XLII where n=1 and R=benzyl is obtained, as shown inScheme 10. Subsequent lithium aluminum hydride reduction reduces theester to the alcohol XLIII, which can then be reacted with a variety ofalkylating agents such as an alkyl iodide, under basic conditions, forexample, sodium hydride in dimethylformamide or tetrahydrofuran. Theresulting ether XLIV can then be carried on to final products asdescribed in Schemes 3-9.

N-Aryl piperazines can be prepared as described in Scheme 11. An arylamine XLV is reacted with bis-chloroethyl amine hydrochloride (XLVI) inrefluxing n-butanol to furnish compounds XLVII. The resultingpiperazines XLVII can then be carried on to final products as describedin Schemes 3-9.

Piperazin-5-ones can be prepared as shown in Scheme 12. Reductiveamination of Boc-protected amino aldehydes XLIX (prepared from I asdescribed previously) gives rise to compound L. This is then reactedwith bromoacetyl bromide under Schotten-Baumann conditions; ring closureis effected with a base such as sodium hydride in a polar aproticsolvent such as dimethylformamide to give LI. The carbamate protectinggroup is removed under acidic conditions such as trifluoroacetic acid inmethylene chloride, or hydrogen chloride gas in methanol or ethylacetate, and the resulting piperazine can then be carried on to finalproducts as described in Schemes 3-9.

The isomeric piperazin-3-ones can be prepared as described in Scheme 13.The imine formed from arylcarboxamides LII and 2-aminoglycinal diethylacetal (LIII) can be reduced under a variety of conditions, includingsodium triacetoxyborohydride in dichloroethane, to give the amine LIV.Amino acids I can be coupled to amines LIV under standard conditions,and the resulting amide LV when treated with aqueous acid intetrahydrofuran can cyclize to the unsaturated LVI. Catalytichydrogenation under standard conditions gives the requisite intermediateLVII, which is elaborated to final products as described in Schemes 3-9.

Access to alternatively substituted piperazines is described in Scheme14. Following deprotection with trifluoroacetic acid, the N-benzylpiperazine V can be acylated with an aryl carboxylic acid. The resultingN-benzyl aryl carboxamide LIX can be hydrogenated in the presence of acatalyst to give the piperazine carboxamide LX which can then be carriedon to final products as described in Schemes 3-9.

Reaction Scheme 15 provides an illustrative example the synthesis ofcompounds of the instant invention wherein the substituents R² and R³are combined to form —(CH₂)_(u)—. For example,1-aminocyclohexane-1-carboxylic acid LXI can be converted to thespiropiperazine LXVI essentially according to the procedures outlined inSchemes 1 and 2. The piperazine intermediate LXIX can be deprotected asbefore, and carried on to final products as described in Schemes 3-9. Itis understood that reagents utilized to provide the substituent Y whichis 2-(naphthyl) and the imidazolylalkyl substituent may be readilyreplaced by other reagents well known in the art and readily availableto provide other N-substituents on the piperazine.

The aldehyde XLIX from Scheme 12 can also be reductively alkylated withan aniline as shown in Scheme 16. The product LXXI can be converted to apiperazinone by acylation with chloroacetyl chloride to give LXXII,followed by base-induced cyclization to LXXIII. Deprotection, followedby reductive alkylation with a protected imidazole carboxaldehyde leadsto LXXV, which can be alkylation with an arylmethylhalide to give theimidazolium salt LXXVI. Final removal of protecting groups by eithersolvolysis with a lower alkyl alcohol, such as methanol, or treatmentwith triethylsilane in methylene chloride in the presence oftrifluoroacetic acid gives the final product LXXVII.

Scheme 17 illustrates the use of an optionally substituted homoserinelactone LXXIX to prepare a Boc-protected piperazinone LXXXII.Intermediate LXXXII may be deprotected and reductively alkylated oracylated as illustrated in the previous Schemes. Alternatively, thehydroxyl moiety of intermediate LXXXII may be mesylated and displaced bya suitable nucleophile, such as the sodium salt of ethane thiol, toprovide an intermediate LXXXIII. Intermediate LXXXII may also beoxidized to provide the carboxylic acid on intermediate LXXXIV, whichcan be utilized form an ester or amide moiety.

Amino acids of the general formula LXXXVI which have a sidechain notfound in natural amino acids may be prepared by the reactionsillustrated in Scheme 18 starting with the readily prepared imine LXXXV.

Schemes 19-22 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art.

The farnesyl transferase inhibitors of formula (II-d) can be synthesizedin accordance with Schemes 23-36, in addition to other standardmanipulations such as ester hydrolysis, cleavage of protecting groups,etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R², R⁶ and R⁸, as shown in theSchemes, represent the substituents R², R³, R⁴, R⁵, R^(6a), R^(6b),R^(6c), R^(6d) and R⁸; although only one such R², R⁶ or R⁸ is present inthe intermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heteroarylmoieties contain multiple substituents. The compounds referred to in theSynopsis of Schemes 23-36 by Roman numerals are numbered startingsequentially with I and ending with XXV.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Aryl-aryl coupling is generally described in “ComprehensiveOrganic Functional Group Transformations,” Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 23-36:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 23-35 illustrate synthesis of the compounds of the formula II-dwhich incorporate a preferred benzylimidazolyl sidechain. In Scheme 23,for example, a biaryl intermediate that is not commercially availablemay be synthesized by methods known in the art. Thus, a suitablysubstituted phenyl boronic acid I may be reacted under Suzuki couplingconditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substitutedhalogenated benzoic acid, such as 4-bromobenzoic acid, to provide thebiaryl carboxylic acid II. The acid may be reduced and the triflate ofthe intermediate alcohol III may be formed in situ and coupled to asuitably substituted benzylimidazolyl IV to provide, after deprotection,the instant compound V.

Schemes 24-27 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 23.Thus, Scheme 24 illustrates the analogous series of biaryl alcoholforming reactions starting with the halogenated biarylaldehyde.

Scheme 25 illustrates the reaction wherein the “terminal” phenyl moietyis employed in the Suzuki coupling as the halogenated reactant. Such acoupling reaction is also compatible when one of the reactantsincorporates a suitably protected hydroxyl functionality as illustratedin Scheme 26.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the biaryl component of the instant compounds, as shown in Scheme27. Thus, a suitably substituted zinc bromide adduct may be coupled to asuitably substituted aryl halide in the presence of nickel (II) toprovide the biaryl VII. The aryl halide and the zinc bromide adduct maybe selected based on the availability of the starting reagents.

Scheme 28 illustrates the preparation of a suitably substitutedbiphenylmethyl bromide which could also be utilized in the reaction withthe protected imidazole as described in Scheme 1.

As illustrated in Scheme 29, the sequence of coupling reactions may bemodified such that the biphenyl bond is formed last. Thus, a suitablysubstituted imidazole may first be alkylated with a suitably substitutedbenzyl halide to provide intermediate VIII. Intermediate VIII can thenundergo Suzuki type coupling to a suitably substituted phenyl boronicacid.

Scheme 30 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 31 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated biaryl moieties to provide the instant compoundsshown.

Compounds of the instant invention wherein the A¹(CR^(1a)₂)_(n)A²(CR^(1a) ₂)_(n) linker is oxygen may be synthesized by methodsknown in the art, for example as shown in Scheme 32. The suitablysubstituted phenol XIV may be reacted with methyl N-(cyano)methanimidateto provide the 4-phenoxyimidazole XV. After selective protection of oneof the imidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 33 illustrates an analogous series of reactions wherein the(CR^(1b) ₂)_(p)X(CR^(1b) ₂)_(p) linker of the instant compounds isoxygen. Thus, a suitably substituted haloaryl alcohol, such as, isreacted with methyl N-(cyano)methanimidate to provide intermediate XVI.Intermediate XVI is then protected and, if desired to form a compound ofa preferred embodiment, alkylated with a suitably protected benzyl. Theintermediate XVII can then be coupled to a second aryl moiety by Suzukichemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹(CR^(1a)₂)_(n)A²(CR^(1a) ₂)_(n) linker is a substituted methylene may besynthesized by the methods shown in Scheme 34. Thus, the N-protectedimidazolyl iodide XVIII is reacted, under Grignard conditions with asuitably protected benzaldehyde to provide the alcohol XIX. Acylation,followed by the alkylation procedure illustrated in the Schemes above(in particular, Scheme 23) provides the instant compound XX. If other R¹substituents are desired, the acetyl moiety can be manipulated asillustrated in the Scheme.

Grignard chemistry may also be employed to form a substituted alkyllinker between the biaryl and the preferred W (imidazolyl) as shown inScheme 35. Similar substituent manipulation as shown in Scheme 34 may beperformed on the fully functionalized compound which incorporates anR^(1b) hydroxyl moiety.

Scheme 36 illustrates reactions wherein the moiety

incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other biheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid (Scheme 14). Grignardchemistry may be utilized, as shown in Scheme 36, to incorporate thebiaryl moiety. Thus, a suitably substituted biaryl Grignard reagent isreacted with an aldehyde to provide the C-alkylated instant compoundXXI. Compound XXI can be deoxygenated by methods known in the art, suchas a catalytic hydrogenation, then deprotected with trifluoroacetic acidin methylene chloride to give the final compound XXII. The final productXXII may be isolated in the salt form, for example, as atrifluoroacetate, hydrochloride or acetate salt, among others. Theproduct diamine XXII can further be selectively protected to obtainXXIII, which can subsequently be reductively alkylated with a secondaldehyde to obtain XXIV. Removal of the protecting group, and conversionto cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

Incorporation of other moieties via the appropriate aldehyde startingmaterial may be performed as illustrated in Scheme 36 and theintermediates manipulated as illustrated above in Schemes 4-9.

The farnesyl transferase inhibitors of formula (II-e) can be synthesizedin accordance with Schemes 37-52,

in addition to other standard manipulations such as ester hydrolysis,cleavage of protecting groups, etc., as may be known in the literatureor exemplified in the experimental procedures. Substituents R², R⁶ andR⁸, as shown in the Schemes, represent the substituents R², R³, R⁴, R⁵,R⁶ and R⁸; although only one such R², R⁶ or R⁸ is present in theintermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heteroarylmoieties contain multiple substituents. The compounds referred to in theSynopsis of Schemes 37-52 by Roman numerals are numbered startingsequentially with I and ending with XXV.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Other reactions useful in the preparation of heteroarylmoieties are described in “Comprehensive Organic Chemistry, Volume 4:Heterocyclic Compounds” ed. P. G. Sammes, Oxford (1979) and referencestherein. Aryl-aryl coupling is generally described in “ComprehensiveOrganic Functional Group Transformations,” Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 37-52:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 37-51 illustrate synthesis of the instant arylheteroarylcompound which incorporate a preferred benzylimidazolyl sidechain. Thus,in Scheme 37, for example, a arylheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a suitably substituted pyridyl boronic acid I may be reacted underSuzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with asuitably substituted halogenated benzoic acid, such as 4-bromobenzoicacid, to provide the arylheteroaryl carboxylic acid II. The acid may bereduced and the triflate of the intermediate alcohol III may be formedin situ and coupled to a suitably substituted benzyl-imidazolyl IV toprovide, after deprotection, the instant compound V.

Schemes 38-41 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 1.Thus, Scheme 38 illustrates the analogous series of arylheteroarylalcohol forming reactions starting with the halogenated arylaldehyde.

Scheme 39 illustrates the reaction wherein the “terminal” heteroarylmoiety is employed in the Suzuki coupling as the halogenated reactant.Such a coupling reaction is also compatible when one of the reactantsincorporates a suitably protected hydroxyl functionality as illustratedin Scheme 40.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the arylheteroaryl component of the instant compounds, as shown inScheme 41. Thus, a suitably substituted zinc bromide adduct may becoupled to a suitably substituted aryl halide in the presence of nickel(II) to provide the arylheteroaryl VII. The heteroaryl halide and thezinc bromide adduct may be selected based on the availability of thestarting reagents.

Scheme 42 illustrates the preparation of the suitably substitutedarylheteroaryl methanol from the pyridyltoluene.

Scheme 43 illustrates the preparation of the suitably substitutedpyrazinylaryl methanol starting with alanine.

As illustrated in Scheme 44, the sequence of coupling reactions may bemodified such that the arylheteroaryl bond is formed last. Thus, asuitably substituted imidazole may first be alkylated with a suitablysubstituted benzyl halide to provide intermediate VIII. IntermediateVIII can then undergo Suzuki type coupling to a suitably substitutedheteroaryl boronic acid.

Scheme 45 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 46 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the arylheteroaryl via an alkylamino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated arylheteroaryl moieties to provide the instantcompounds shown.

Compounds of the instant invention wherein the A¹(CR^(1a)₂)_(n)A²(CR^(1a) ₂)_(n) linker is oxygen may be synthesized by methodsknown in the art, for example as shown in Scheme 47. The suitablysubstituted phenol XIV may be reacted with methyl N-(cyano)methanimidateto provide the 4-phenoxyimidazole XV. After selective protection of oneof the imidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the phenylmethylimidazoles hereinabove.

Scheme 48 illustrates an analogous series of reactions wherein the(CR^(1b) ₂)_(p)X(CR^(1b) ₂)_(p) linker of the instant compounds isoxygen. Thus, a suitably substituted haloaryl alcohol, such as4-bromophenol, is reacted with methyl N-(cyano)methanimidate to provideintermediate XVI. Intermediate XVI is then protected and, if desired toform a compound of a preferred embodiment, alkylated with a suitablyprotected benzyl. The intermediate XVII can then be coupled to aheteroaryl moiety by Suzuki chemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹(CR^(1a)₂)_(n)A²(CR^(1a) ₂)_(n) linker is a substituted methylene may besynthesized by the methods shown in Scheme 49. Thus, the N-protectedimidazolyl iodide XVIII is reacted, under Grignard conditions with asuitably protected benzaldehyde to provide the alcohol XIX. Acylation,followed by the alkylation procedure illustrated in the Schemes above(in particular, Scheme 37) provides the instant compound XX. If other R¹substituent s are desired, the acetyl moiety can be manipulated asillustrated in the Scheme.

Addition of various nucleophiles to an imidazolyl aldehyde may also beemployed to form a substituted alkyl linker between the arylheteroaryland the preferred W (imidazolyl) as shown in Scheme 50. Thus ahalogenated arylheteroaryl, such as 4-(3-pyridyl)bromo-benzene, mayundergo metal halogen exchange followed by reaction with a suitablysubstituted imidazolyl aldehyde and acetylation to form the alcohol.Then, similar substituent manipulation as shown in Scheme 49 may beperformed on a fully functionalized compound which incorporates an R²hydroxyl moiety.

Scheme 51 illustrates the synthesis of a suitably substitutedpyrimidinebromobenzene, which may be employed in the reactionillustrated in Scheme 49. This reaction and other reactions useful inthe preparation of heteroaryl moieties are described in “ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds” ed. P. G. Sammes,Oxford (1979).

Schemes 52 illustrates reactions wherein the moiety

incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other arylheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid. Metalation chemistrymay be utilized, as shown in Scheme 52, to incorporate thearylheteroaryl moiety. Thus, a suitably substituted arylheteroaryllithium reagent, prepared in situ, is reacted with an aldehyde toprovide the C-alkylated instant compound XXI. Compound XXI can bedeoxygenated by methods known in the art, such as a catalytichydrogention, then deprotected with trifluoroacetic acid in methylenechloride to give the final compound XXII. The final product XXII may beisolated in the salt form, for example, as a trifluoroacetate,hydrochloride or acetate salt, among others. The product diamine XXIIcan further be selectively protected to obtain XXIII, which cansubsequently be reductively alkylated with a second aldehyde to obtainXXIV. Removal of the protecting group, and conversion to cyclizedproducts such as the dihydroimidazole XXV can be accomplished byliterature procedures.

Incorporation of other moieties via the appropriate aldehyde startingmaterial may be performed as illustrated in Scheme 52 and theintermediates manipulated as illustrated above in Schemes 4-9.

The farnesyl transferase inhibitors of formula (II-f) can be synthesizedin accordance with Schemes 53-66, in addition to other standardmanipulations such as ester hydrolysis, cleavage of protecting groups,etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R³, R⁶ and R⁸, as shown in theSchemes, represent the substituents R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c),R^(6d), R^(6e) and R⁸; although only one such R³, R⁶ or R⁸ is present inthe intermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heteroarylmoieties contain multiple substituents. The compounds referred to in theSynopsis of Schemes 53-66 by Roman numerals are numbered startingsequentially with I and ending with XXX.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. The reactions described in the Schemes are illustrativeonly and are not meant to be limiting. Other reactions useful in thepreparation of heteroaryl moieties are described in “ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds” ed. P. G. Sammes,Oxford (1979) and references therein. Aryl-aryl coupling is generallydescribed in “Comprehensive Organic Functional Group Transformations,”Katritsky et al. eds., pp 472-473, Pergamon Press (1995).

Synopsis of Schemes 53-66:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 53-64 illustrate synthesis of the instant aryl-heteroarylcompound which incorporate a preferred benzylimidazolyl sidechain. Thus,in Scheme 53, for example, a arylheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a suitably substituted phenyl boronic acid I may be reacted underSuzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with asuitably substituted halogenated nicotinic acid, such as4-bromonicotinic acid, to provide the arylheteroaryl carboxylic acid II.The acid may be reduced and the triflate of the intermediate alcohol IIImay be formed in situ and coupled to a suitably substitutedbenzylimidazolyl IV to provide, after deprotection, the instant compoundV.

Schemes 54-55 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 53.Thus, Scheme 54 illustrates the analogous series of arylheteroarylalcohol forming reactions starting with the methyl nicotinate boronicacid and the “terminal” phenyl moiety employed in the Suzuki coupling asthe halogenated reactant. Such a coupling reaction is also compatiblewhen one of the reactants incorporates a suitably protected hydroxylfunctionality as illustrated in Scheme 55.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the arylheteroaryl component of the instant compounds, as shown inScheme 56. Thus, a suitably substituted zinc bromide adduct may becoupled to a suitably substituted heteroaryl halide in the presence ofnickel (II) to provide the arylheteroaryl VII. The heteroaryl halide andthe zinc bromide adduct may be selected based on the availability of thestarting reagents.

Scheme 57 illustrates the preparation of a suitably substituted3-hydroxymethyl-5-phenyl pyridine which could also be utilized in thereaction with the protected imidazole as described in Scheme 53. AnAlternative preparation of a suitably substituted5-hydroxymethyl-2-phenyl pyridine is also illustrated.

As illustrated in Scheme 58, the sequence of coupling reactions may bemodified such that the aryl-heteroaryl bond is formed last. Thus, asuitably substituted imidazole may first be alkylated with a suitablysubstituted benzyl halide to provide intermediate VIII. IntermediateVIII can then undergo Suzuki type coupling to a suitably substitutedphenyl boronic acid.

Scheme 59 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 60 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated arylheteroaryl moieties to provide the instantcompounds shown.

Compounds of the instant invention wherein the A¹(CR² ₂)_(n)A²(CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 61. The suitably substituted phenol XIVmay be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 62 illustrates an analogous series of reactions wherein the (CR²₂)_(p)X(CR² ₂)_(p) linker of the instant compounds is oxygen. Thus, asuitably substituted halopyridinol, such as 3-chloro-2-pyridinol, isreacted with methyl N-(cyano)methanimidate to provide intermediate XVI.Intermediate XVI is then protected and, if desired to form a compound ofa preferred embodiment, alkylated with a suitably protected benzyl. Theintermediate XVII can then be coupled to a aryl moiety by Suzukichemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 63. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 53) provides the instant compound XX. If other R¹ substituentsare desired, the acetyl moiety can be manipulated as illustrated in theScheme.

Addition of various nucleophiles to an imidazolyl aldehyde may also beemployed to form a substituted alkyl linker between the biheteroaryl andthe preferred W (imidazolyl) as shown in Scheme 64. Thus a suitablysubstituted phenyl lithium can be reacted with pyridine to form the2-substituted N-lithio-1,2-dihydropyridine XXa. Intermediate XXa canthen react with a aldehyde to provide a suitably substituted instantcompound. Similar substituent manipulation as shown in Scheme 63 may beperformed on the fully functionalized compound which incorporates an R²hydroxyl moiety.

Scheme 65 illustrate reactions wherein the moiety

incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other arylheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid. Lithioheteroarylchemistry may be utilized, as shown in Scheme 65, to incorporate thearylheteroaryl moiety. Thus, a suitably substituted arylheteroarylN-lithio reagent is reacted with an aldehyde to provide the C-alkylatedinstant compound XXI. Compound XXI can be deoxygenated by methods knownin the art, such as a catalytic hydrogention, then deprotected withtrifluoroacetic acid in methylene chloride to give the final compoundXXII. The final product XXII may be isolated in the salt form, forexample, as a trifluoroacetate, hydrochloride or acetate salt, amongothers. The product diamine XXII can further be selectively protected toobtain XXIII, which can subsequently be reductively alkylated with asecond aldehyde to obtain XXIV. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

If the arylheteroaryl subunit reagent is reacted with an aldehyde whichalso has a protected hydroxyl group, such as XXVI in Scheme 66, theprotecting groups can be subsequently removed to unmask the hydroxylgroup. The alcohol can be oxidized under standard conditions to e.g. analdehyde, which can then be reacted with a variety of organometallicreagents such as alkyl lithium reagents, to obtain secondary alcoholssuch as XXX.

Incorporation of other moieties via the appropriate aldehyde startingmaterial may be performed as illustrated in Scheme 65-66 and theintermediates manipulated as illustrated above in Schemes 4-9.

The farnesyl transferase inhibitors of formula (II-g) can be synthesizedin accordance with Schemes 67-78,

in addition to other standard manipulations such as ester hydrolysis,cleavage of protecting groups, etc., as may be known in the literatureor exemplified in the experimental procedures. Substituents R³, R⁶ andR⁸, as shown in the Schemes, represent the substituents R³, R⁴, R⁵, R⁶and R⁸; although only one such R³, R⁶ or R⁸ is present in theintermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heteroarylmoieties contain multiple substituents. The compounds referred to in theSynopsis of Schemes 67-78 by Roman numerals are numbered startingsequentially with I and ending with XX.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. The reactions described in the Schemes are illustrativeonly and are not meant to be limiting. Other reactions useful in thepreparation of heteroaryl moieties are described in “ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds” ed. P. G. Sammes,Oxford (1979) and references therein. Aryl-aryl coupling is generallydescribed in “Comprehensive Organic Functional Group Transformations,”Katritsky et al. eds., pp 472-473, Pergamon Press (1995).

Synopsis of Schemes 67-78:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 67-78 illustrate synthesis of the instant biheteroaryl compoundwhich incorporate a preferred benzylimidazolyl sidechain. Thus, inScheme 67, for example, a biheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a suitably substituted pyridyl boronic acid I may be reacted underSuzuki coupling conditions (Pure Appl. Chem., 63:419 (1991)) with asuitably substituted halogenated nicotinic acid, such as4-bromo-nicotinic acid, to provide the biheteroaryl carboxylic acid II.The acid may be reduced and the triflate of the intermediate alcohol IIImay be formed in situ and coupled to a suitably substitutedbenzylimidazolyl IV to provide, after deprotection, the instant compoundV.

Schemes 68-71 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 67.Thus, Scheme 68 illustrates the analogous series of biheteroaryl alcoholforming reactions starting with the methyl nicotinate boronic acid andthe “terminal” heteroaryl moiety employed in the Suzuki coupling as thehalogenated reactant. Such a coupling reaction is also compatible whenone of the reactants incorporates a suitably protected hydroxylfunctionality as illustrated in Scheme 69.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the biheteroaryl component of the instant compounds, as shown inScheme 70. Thus, a suitably substituted zinc bromide adduct may becoupled to a suitably substituted heteroaryl halide in the presence ofnickel (II) to provide the biheteroaryl VII. The heteroaryl halide andthe zinc bromide adduct may be selected based on the availability of thestarting reagents.

Scheme 71 illustrates the preparation of the pyridylmethanolintermediate starting with the 3-methyl pyridine.

As illustrated in Scheme 72, the sequence of coupling reactions may bemodified such that the heteroaryl-heteroaryl bond is formed last. Thus,a suitably substituted imidazole may first be alkylated with a suitablysubstituted benzyl halide to provide intermediate VIII. IntermediateVIII can then undergo Suzuki type coupling to a suitably substitutedpyridyl boronic acid.

Scheme 73 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole IX may be selectivelyiodinated to provide the 5-iodoimidazole X. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate XI. Intermediate XI can then undergo the alkylationreactions that were described hereinabove.

Scheme 74 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkyl-imidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated biheteroaryl moieties to provide the instant compoundsshown.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 75. The suitably substituted phenol XIVmay be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 76 illustrates an analogous series of reactions wherein the (CR²₂)_(p)X(CR² ₂)_(p) linker of the instant compounds is oxygen. Thus, asuitably substituted halopyridinol, such as 3-chloro-2-pyridinol, isreacted with methyl N-(cyano)methanimidate to provide intermediate XVI.Intermediate XVI is then protected and, if desired to form a compound ofa preferred embodiment, alkylated with a suitably protected benzyl. Theintermediate XVII can then be coupled to a heteroaryl moiety by Suzukichemistry to provide the instant compound.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 77. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 67) provides the instant compound XX. If other R¹ substituent sare desired, the acetyl moiety can be manipulated as illustrated in theScheme.

Scheme 78 illustrates the use of halogenated 2-amino-pyrimidine in thepreparation of compounds of the instant invention.

The farnesyl transferase inhibitors of formula (II-j) can be synthesizedin accordance with Schemes 79-88, in addition to other standardmanipulations such as ester hydrolysis, cleavage of protecting groups,etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R³, R⁶ and R⁸, as shown in theSchemes, represent the substituents R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c),R^(6d), R^(6e) and R⁸; although only one such R³, R⁶ or R⁸ is present inthe intermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heterocyclicmoieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. The reactions described in the Schemes are illustrativeonly and are not meant to be limiting. Other reactions useful in thepreparation of heteroaryl moieties are described in “ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds” ed. P. G. Sammes,Oxford (1979) and references therein.

Synopsis of Schemes 79-88:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures. Schemes 79-88illustrate synthesis of the instant bicyclic compounds which incorporatea preferred benzylimidazolyl side chain. Thus, in Scheme 79, forexample, a bicyclic intermediate that is not commercially available maybe synthesized by methods known in the art. Thus, a suitably substitutedpyridinone 1 may be reacted under coupling conditions with a suitablysubstituted iodobenzyl alcohol to provide the intermediate alcohol 2.The intermediate alcohol 2 may converted to the corresponding bromide 3.The bromide 3 may be coupled to a suitably substituted benzylimidazolyl4 to provide, after deprotection, the instant compound 5.

Schemes 80-82 illustrate methods of synthesizing related or analogouskey alcohol intermediates, which can then be processed as described inScheme 79. Thus, Scheme 80 illustrates pyridinonyl-pyridyl alcoholforming reactions starting with the suitably substituted iodonicotinate6.

Scheme 81 illustrates preparation of the intermediate alcohol 9 whereinthe terminal lactam ring is saturated. Acylation of a suitablysubstituted 4-aminobenzyl alcohol 7 with a suitably substitutedbrominated acyl chloride provides the bisacylated intermediate 8.Closure of the lactam ring followed by saponification of the remainingacyl group provides the intermediate alcohol. Preparation of thehomologous saturated lactam 10 is illustrated in Scheme 82.

Scheme 83 illustrates the synthesis of the alcohol intermediate 13 whichincorporates a terminal pyrazinone moiety. Thus, the amide of a suitablysubstituted amino acid 11 is formed and reacted with glyoxal to form thepyrazine 12, which then undergoes the Ullmann coupling to formintermediate 13.

Scheme 84 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole 14 may be selectivelyiodinated to provide the 5-iodoimidazole 15. That imidazole may then beprotected and coupled to a suitably substituted benzyl moiety to provideintermediate 16. Intermediate 16 can then undergo the alkylationreactions that were described hereinabove.

Scheme 85 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the bicyclic moiety via analkyl amino, sulfonamide or amide linker. Thus, the4-aminoalkylimidazole 17, wherein the primary amine is protected as thephthalimide, is selectively alkylated then deprotected to provide theamine 18. The amine 18 may then react under conditions well known in theart with various activated bicyclic moieties to provide the instantcompounds shown.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 86. The suitably substituted phenol 19may be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole 20. After selective protection of one of theimidazolyl nitrogens, the intermediate 21 can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 87. Thus, the N-protected imidazolyl iodide 22is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol 23. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 79) provides the instant compound 24. If other R¹ substituentsare desired, the acetyl moiety can be manipulated as illustrated in theScheme.

Scheme 88 illustrates incorporation of an acetyl moiety as the (CR²₂)_(p)X(CR² ₂)_(p) linker of the instant compounds. Thus the readilyavailable methylphenone 25 undergoes the Ullmann reaction and the acetylis brominated to provide intermediate 26. Reaction with the imidazolylreagent 4 provides, after deprotection, the instant compound 27.

The farnesyl transferase inhibitors of formula (II-k) can be synthesizedin accordance with Schemes 89-97, in addition to other standardmanipulations such as ester hydrolysis, cleavage of protecting groups,etc., as may be known in the literature or exemplified in theexperimental procedures. Substituents R³, R⁶ and R⁸, as shown in theSchemes, represent the substituents R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c),R^(6d), R^(6e) and R⁸; although only one such R³, R⁶ or R⁸ is present inthe intermediates and products of the schemes, it is understood that thereactions shown are also applicable when such aryl or heterocyclicmoieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. The reactions described in the Schemes are illustrativeonly and are not meant to be limiting. Other reactions useful in thepreparation of heteroaryl moieties are described in “ComprehensiveOrganic Chemistry, Volume 4: Heterocyclic Compounds” ed. P. G. Sammes,Oxford (1979) and references therein.

Synopsis of Schemes 89-97:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures. Schemes 89-96illustrate synthesis of the instant bicyclic compounds which incorporatea preferred benzylimidazolyl sidechain. Thus, in Scheme 89, for example,a bicyclic intermediate that is not commercially available may besynthesized by methods known in the art. Thus, a suitably substitutedpyridinonyl alcohol 29 may be synthesized starting from thecorresponding isonicotinate 28 according to procedures described byBoekelhiede and Lehn (J. Org. Chem., 26:428-430 (1961)). The alcohol isthen protected and reacted under Ullmann coupling conditions with asuitably substituted phenyl iodide, to provide the intermediate bicyclicalcohol 30. The intermediate alcohol 30 may converted to thecorresponding bromide 31. The bromide 31 may be coupled to a suitablysubstituted benzylimidazolyl 32 to provide, after deprotection, theinstant compound 33.

Schemes 90-92 illustrate methods of synthesizing related or alcoholintermediates, which can then be processed as described in Scheme 89.Thus, Scheme 90 illustrates preparation of a pyridyl-pyridinonyl alcoholand thienylpyridinonyl alcohol starting with the suitably substitutedhalogenated heterocycles.

Scheme 91 illustrates preparation of the intermediate bromide 36 whereinthe preferred pyridinone is replaced by a saturated lactam. Acylation ofa suitably substituted aniline 34 with a suitably substituted brominatedacyl chloride provides the acylated intermediate 35. Closure of thelactam ring provides the intermediate alcohol, which is converted to thebromide as described above.

Scheme 92 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the instant compound. Thus, areadily available 4-substituted imidazole 37 may be selectivelyiodinated to provide the 5-iodoimidazole 38. That imidazole 38 may thenbe protected and coupled to a suitably substituted benzyl moiety toprovide intermediate 39. Intermediate 39 can then undergo the alkylationreactions that were described hereinabove.

Scheme 93 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the biaryl via an alkyl amino,sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole 40, whereinthe primary amine is protected as the phthalimide, is selectivelyalkylated then deprotected to provide the amine 41. The amine 41 maythen react under conditions well known in the art with various activatedarylheteroaryl moieties to provide the instant compounds shown.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is oxygen may be synthesized by methods known in the art,for example as shown in Scheme 94. The suitably substituted phenol 42may be reacted with methyl N-(cyano)methanimidate to provide the4-phenoxyimidazole 43. After selective protection of one of theimidazolyl nitrogens, the intermediate 44 can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Compounds of the instant invention wherein the A¹(CR¹ ₂)_(n)A²(CR¹₂)_(n) linker is a substituted methylene may be synthesized by themethods shown in Scheme 95. Thus, the N-protected imidazolyl iodide 45is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol 46. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 89) provides the instant compound 47. If other R¹ substituentsare desired, the acetyl moiety can be manipulated as illustrated in theScheme.

Scheme 96 illustrates incorporation of an acetyl moiety as the (CR²₂)_(p)X(CR² ₂)_(p) linker of the instant compounds. Thus, the suitablysubstituted acetyl pyridine 48 is converted to the correspondingpyridinone and undergoes the Ullmann reaction with a suitablysubstituted phenyl iodide. The acetyl is then brominated to provideintermediate 49. Reaction with the imidazolyl reagent 32 provides, afterdeprotection, the instant compound 50.

Scheme 97 illustrate reactions wherein the moiety

incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in the Schemes,and other pyridinonecarbocyclic and pyridinoneheterocyclic intermediatesobtained commercially or readily synthesized, can be coupled with avariety of aldehydes. The aldehydes can be prepared by standardprocedures, such as that described by O. P. Goel, U. Krolls, M. Stierand S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid. Knochel chemistry may be utilized, as shown inScheme 97, to incorporate the arylpyridinone moiety. Thus, a suitablysubstituted 4-(bromo)-pyridine is converted to the correspondingpyridinone 51 as described above and the pyridinone is coupled to asuitably substituted phenyl iodide as previously described above. Theresulting bromide 52 is treated with zinc(O) and the resulting zincbromide reagent 53 is reacted with an aldehyde to provide theC-alkylated instant compound 54. Compound 54 can be deoxygenated bymethods known in the art, such as a catalytic hydrogention, thendeprotected with trifluoroacetic acid in methylene chloride to give thefinal compound 55. The compound 55 may be isolated in the salt form, forexample, as a trifluoroacetate, hydrochloride or acetate salt, amongothers. The product diamine 55 can further be selectively protected toobtain 56, which can subsequently be reductively alkylated with a secondaldehyde to obtain compound 57. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole 58 can beaccomplished by literature procedures.

The farnesyl transferase inhibitors of formula (II-i) can be synthesizedin accordance with Reaction Schemes, in addition to other standardmanipulations such as ester hydrolysis, cleavage of protecting groups,etc., as may be known in the literature or exemplified in theexperimental procedures. Some key reactions utilized to form theaminodiphenyl moiety of the instant compounds are shown.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Reaction Schemes.

Reaction Schemes A-P describe the preparation of appropriatelysubstituted aniline intermediates that may be further functionalized bythe methods described in Reaction Schemes Q-Y to provide the compoundsof the instant invention.

Reaction Schemes A-D illustrate use of Ullman reactions to providediphenyl ethers, amines and sulfides from readily available fullysubstituted phenols/thiophenols/anilines and aryl halides. In suchsyntheses, the desired amine moiety is typically masked as a nitro groupwhich is subsequently reduced by techniques well known in the art. Analternative synthesis of the diphenyl ethers which employs para-nitrofluorobenzene is shown in Reaction Scheme E.

Reaction Scheme F illustrates standard acid-amine coupling to providethe fully substituted N-phenylbenzamides. Reaction Scheme G illustratesformation of the aminomethyl spacer via a reductive amination of asuitably substituted benzaldehyde.

Reaction Scheme H illustrates coupling of suitably substituted anilineswith readily available phenylsulfonyl chlorides. Access toaminobenzophenones is illustrated in Reaction Scheme I, which alsoillustrates the reduction of the carbonyl to provide the unsubstitutedmethyl spacer. An alternative method of forming the benzophenoneintermediates is illustrated in Reaction Scheme J. Also shown inReaction Scheme J is reductive amination of the resulting carbonyl toprovide the amine substituted methyl spacer. Another method of formingthe benzophenone intermediates, illustrated in Reaction Scheme K, is aStille reaction with an aryl stannane.

Reaction Schemes L and M illustrate palladium mediated formation ofolefin and acetylene spacer units. Reaction Scheme N illustratesformation of an appropriately substituted benzyl ether. Reaction SchemeP illustrates the use of the Claisen rearrangement to provide methylspacers having substituents such as a vinyl group which can be furtherfunctionalized.

Reaction Schemes Q-S illustrate reactions wherein thenon-sulfhydryl-containing moiety(ies) of the compounds of the instantinvention is attached to the aminodiphenyl subunit to provide theinstant compounds.

Thus, the aminodiphenyl subunit can be reductively alkylated withaldehydes such as 1-trityl-4-carboxaldehyde or1-trityl-4-imidazolylacetaldehyde, to give products such as VIII(Reaction Scheme Q). The trityl protecting group can be removed fromVIII to give IX, or alternatively, VIII can first be treated with analkyl halide then subsequently deprotected to give the alkylatedimidazole X. Alternatively, the aminomethylbenzamide subunit can beacylated or sulfonylated by standard techniques.

The imidazole acetic acid XI can be converted to the acetate XIII bystandard procedures, and XIII can be first reacted with an alkyl halide,then treated with refluxing methanol to provide the regiospecificallyalkylated imidazole acetic acid ester XIV. Hydrolysis and reaction withthe aminodiphenyl subunit in the presence of condensing reagents such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylatedproducts such as XV. Coupling reactions with other suitably substitutedaldehydes may be performed as illustrated in Schemes 3 and 6-9hereinabove.

Reaction Scheme S illustrates a one pot synthesis of an instant compoundwherein the N-terminus nitrogen is substituted with two differentnon-sulfhydryl-containing moieties. Thus, the aminodiphenyl subunit istreated with one equivalent of an appropriate aldehyde and, after thereductive adduct has been formed, the in situ intermediate is treatedwith an equivalent of a different aldehyde.

wherein, in the above Reaction Schemes, R′ is R^(1a); R″ is(R⁶)_(r)—V-A¹—(CR^(1a))_(n)—; R′″ is selected such that R′″CH₂— is R⁸;and R^(x) and R^(y) are selected such that R^(x)CH₂— and R^(y)CH₂— areeither R⁴ or R⁵.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

The standard workup referred to in the examples refers to solventextraction and washing the organic solution with 10% citric acid, 10%sodium bicarbonate and brine as appropriate. Solutions were dried oversodium sulfate and evaporated in vacuo on a rotary evaporator.

Example 1(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinoneDihydrochloride

Step A: 1-triphenylmethyl-4-(hydroxymethyl)-imidazole

To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260mmol) in 250 mL of dry DMF at room temperature was added triethylamine(90.6 mL, 650 mmol). A white solid precipitated from the solution.Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was addeddropwise. The reaction mixture was stirred for 20 hours, poured overice, filtered, and washed with ice water. The resulting product wasslurried with cold dioxane, filtered, and dried in vacuo to provide thetitled product as a white solid which was sufficiently pure for use inthe next step.

Step B: 1-triphenylmethyl-4-(acetoxymethyl)-imidazole

Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mLof pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, andthe reaction was stirred for 48 hours during which it becamehomogeneous. The solution was poured into 2 L of EtOAc, washed withwater (3×1 L), 5% aq. HCl soln. (2×1 L), sat. aq. NaHCO₃, and brine,then dried (Na₂SO₄), filtered, and concentrated in vacuo to provide thecrude product. The acetate was isolated as a white powder which wassufficiently pure for use in the next reaction.

Step C: 1-(4-cyanobenzyl)-5-(acetoxymethyl)-imidazole Hydrobromide

A solution of the product from Step B (85.8 g, 225 mmol) andα-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirredat 60° C. for 20 hours, during which a pale yellow precipitate formed.The reaction was cooled to room temperature and filtered to provide thesolid imidazolium bromide salt. The filtrate was concentrated in vacuoto a volume 200 mL, reheated at 60° C. for two hours, cooled to roomtemperature, and filtered again. The filtrate was concentrated in vacuoto a volume 100 mL, reheated at 60° C. for another two hours, cooled toroom temperature, and concentrated in vacuo to provide a pale yellowsolid. All of the solid material was combined, dissolved in 500 mL ofmethanol, and warmed to 60° C. After two hours, the solution wasreconcentrated in vacuo to provide a white solid which was trituratedwith hexane to remove soluble materials. Removal of residual solvents invacuo provided the titled product hydrobromide as a white solid whichwas used in the next step without further purification.

Step D: 1-(4-cyanobenzyl)-5-(hydroxymethyl)-imidazole

To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of3:1 THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g,450 mmol). After one hour, the reaction was concentrated in vacuo,diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO₃ andbrine. The solution was then dried (Na₂SO₄), filtered, and concentratedin vacuo to provide the crude product as a pale yellow fluffy solidwhich was sufficiently pure for use in the next step without furtherpurification.

Step E: 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde

To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL ofDMSO at room temperature was added triethylamine (56 mL, 402 mmol), thenSO₃-pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reactionwas poured into 2.5 L of EtOAc, washed with water (4×1 L) and brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to provide thealdehyde as a white powder which was sufficiently pure for use in thenext step without further purification.

Step F:(S)-2-(tert-butoxycarbonylamino)-N-methoxy-N-methyl-4-(methylthio)butanamide

L-N-Boc-methionine (30.0 g, 0.120 mol), N,O-dimethyl-hydroxylaminehydrochloride (14.1 g, 0.144 mol), EDC hydrochloride (27.7 g, 0.144 mol)and HOBT (19.5 g, 0.144 mol) were stirred in dry DMF (300 mL) at 20° C.under nitrogen. More N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23mmol) was added to obtain pH 7-8. The reaction was stirred overnight,the DMF distilled to half the original volume under high vacuum, and theresidue partitioned between ethyl acetate and sat. NaHCO₃ soln. Theorganic phase was washed with saturated sodium bicarbonate, water, 10%citric acid, and brine, and dried with sodium sulfate. The solvent wasremoved in vacuo to give the title compound.

Step G: (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanal

A suspension of lithium aluminum hydride (5.02 g, 0.132 mol) in ether(500 mL) was stirred at room temperature for one hour. The solution wascooled to −50° C. under nitrogen, and a solution of the product fromStep F (39.8 g, ca. 0.120 mol) in ether (200 mL) was added over 30 min,maintaining the temperature below −40° C. When the addition wascomplete, the reaction was warmed to 5° C., then recooled to −45° C.Analysis by tlc revealed incomplete reaction. The solution was rewarmedto 5° C, stirred for 30 minutes, then cooled to −50° C. A solution ofpotassium hydrogen sulfate (72 g, 0.529 mol) in 200 mL water was slowlyadded, maintaining the temperature below −20° C. The mixture was warmedto 5° C., filtered through Celite, and concentrated in vacuo to providethe title aldehyde.

Step H:(S)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-4-(methylthio)butanamine

To a solution of 3-chloroaniline (10.3 mL, 97.4 mmol), the product fromStep G (23.9 g, 97.4 mmol), and acetic acid (27.8 mL, 487 mmol) indichloroethane (250 mL) under nitrogen was added sodiumtriacetoxyborohydride (41.3 g, 195 mmol). The reaction was stirredovernight, then quenched with saturated sodium bicarbonate solution. Thesolution was diluted with CHCl₃, and the organic phase was washed withwater, 10% citric acid and brine. The solution was dried over sodiumsulfate and concentrated in vacuo to provide the crude product (34.8 g)which was chromatographed on silica gel with 20% ethyl acetate in hexaneto obtain the title compound.

Step I:(S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[2-(methylthio)ethyl]piperazin-2-one

A solution of the product from Step H (22.0 g, 63.8 mmol) in ethylacetate (150 mL) was vigorously stirred at 0° C. with saturated sodiumbicarbonate (150 mL). Chloroacetyl chloride (5.6 mL, 70.2 mmol) wasadded dropwise, and the reaction stirred at 0° C. for 2 h. The layerswere separated, and the ethyl acetate phase was washed with 10% citricacid and saturated brine, and dried over sodium sulfate. Afterconcentration in vacuo, the resulting crude product (27.6 g) wasdissolved in DMF (300 mL) and cooled to 0° C. under argon. Cesiumcarbonate (63.9 g, 196 mmol) was added, and the reaction was stirred fortwo days, allowing it to warm to room temperature. Another portion ofcesium carbonate (10 g, 30 mmol) was added, and the reaction was stirredfor 16 hours. The DMF was distilled in vacuo, and the residuepartitioned between ethyl acetate and water. The organic phase waswashed with saturated brine, and dried over sodium sulfate. The crudeproduct was chromatographed on silica gel with 20-25% ethyl acetate inhexane to obtain the title compound.

Step J:(S)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[2-(methanesulfonyl)ethyl]piperazin-2-one

A solution of the product from Step 1 (14.2 g, 37 mmol) in methanol (300mL) was cooled to 0° C., and a solution of magnesium monoperoxyphthalate(54.9 g, 111 mmol) in 210 mL MeOH was added over 20 minutes. The icebath was removed, and the solution was allowed to warm to roomtemperature. After 45 minutes, the reaction was concentrated in vacuo tohalf the original volume, then quenched by the addition of 2N Na₂S₂O₃soln. The solution was poured into EtOAc and sat NaHCO₃ solution, andthe organic layer was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to provide the crude sulfone. This material waschromatographed on silica gel with 60-100% ethyl acetate in hexane toobtain the titled compound.

Step K:(S)-1-(3-chlorophenyl)-5-[2-(methanesulfonyl)ethyl]piperazin-2-one

Through a solution of Boc-protected piperazinone from Step J (1.39 g,3.33 mmol) in 30 mL of EtOAc at 0° C. was bubbled anhydrous HCl gas. Thesaturated solution was stirred for 35 minutes, then concentrated invacuo to provide the hydrochloride salt as a white powder. This materialwas suspended in EtOAc and treated with dilute aqueous NaHCO₃ solution.The aqueous phase was extracted with EtOAc, and the combined organicmixture was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting amine was reconcentrated fromtoluene to provide the titled material suitable for use in the nextstep.

Step L:(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolyl-methyl]-5-[2-(methanesulfonyl)-ethyl]-2-piperazinoneDihydrochloride

To a solution of the amine from Step K (898 mg, 2.83 mmol) and imidazolecarboxaldehyde from Step E (897 mg, 4.25 mmol) in 15 mL of1,2-dichloroethane was added sodium triacetoxyborohydride (1.21 g, 5.7mmol). The reaction was stirred for 23 hours, then quenched at 0° C.with sat. NaHCO₃ solution. The solution was poured into CHCl₃, and theaqueous layer was back-extracted with CHCl₃. The combined organics werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The resulting product was purified by silica gel chromatography(95:5:0.5-90:10:0 EtOAc:MeOH:NH₄Cl), and the resultant product was takenup in EtOAc/methanol and treated with 2.1 equivalents of 1 M HCl/ethersolution. After concentrated in vacuo, the product dihydrochloride wasisolated as a white powder.

Example 21-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolyl-methyl]-2-piperazinoneDihydrochloride

Step A: N-(3-chlorophenyl)ethylenediamine Hydrochloride

To a solution of 3-chloroaniline (30.0 mL, 284 mmol) in 500 mL ofdichloromethane at 0° C. was added dropwise a solution of 4 N HCl in1,4-dioxane (80 mL, 320 mmol HCl). The solution was warmed to roomtemperature, then concentrated to dryness in vacuo to provide a whitepowder. A mixture of this powder with 2-oxazolidinone (24.6 g, 282 mmol)was heated under nitrogen atmosphere at 160° C. for 10 hours, duringwhich the solids melted, and gas evolution was observed. The reactionwas allowed to cool, forming the crude diamine hydrochloride salt as apale brown solid.

Step B: N-(tert-butoxycarbonyl)-N′-(3-chlorophenyl)ethylenediamine

The amine hydrochloride from Step A (ca. 282 mmol, crude materialprepared above) was taken up in 500 mL of THF and 500 mL of sat. aq.NaHCO₃ soln., cooled to 0° C., and di-tert-butylpyrocarbonate (61.6 g,282 mmol) was added. After 30 h, the reaction was poured into EtOAc,washed with water and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to provide the titled carbamate as a brown oil which was usedin the next step without further purification.

Step C:N-[2-(tert-butoxycarbamoyl)ethyl]-N-(3-chlorophenyl)-2-chloroacetamide

A solution of the product from Step B (77 g, ca. 282 mmol) andtriethylamine (67 mL, 480 mmol) in 500 mL of CH₂Cl₂ was cooled to 0° C.Chloroacetyl chloride (25.5 mL, 320 mmol) was added dropwise, and thereaction was maintained at 0° C. with stirring. After 3 h, anotherportion of chloroacetyl chloride (3.0 mL) was added dropwise. After 30min, the reaction was poured into EtOAc (2 L) and washed with water,sat. aq. NH₄Cl soln, sat. aq. NaHCO₃ soln., and brine. The solution wasdried (Na₂SO₄), filtered, and concentrated in vacuo to provide thechloroacetamide as a brown oil which was used in the next step withoutfurther purification.

Step D: 4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-2-piperazinone

To a solution of the chloroacetamide from Step C (ca. 282 mmol) in 700mL of dry DMF was added K₂CO₃ (88 g, 0.64 mol). The solution was heatedin an oil bath at 70-75° C. for 20 hours, cooled to room temperature,and concentrated in vacuo to remove ca. 500 mL of DMF. The remainingmaterial was poured into 33% EtOAc/hexane, washed with water and brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to provide theproduct as a brown oil. This material was purified by silica gelchromatography (25-50% EtOAc/hexane) to yield pure product, along with asample of product (ca. 65% pure by HPLC) containing a less polarimpurity.

Step E: 1-(3-chlorophenyl)-2-piperazinone

Through a solution of Boc-protected piperazinone from Step D (17.19 g,55.4 mmol) in 500 mL of EtOAc at −78° C. was bubbled anhydrous HCl gas.The saturated solution was warmed to 0° C., and stirred for 12 hours.Nitrogen gas was bubbled through the reaction to remove excess HCl, andthe mixture was warmed to room temperature. The solution wasconcentrated in vacuo to provide the hydrochloride as a white powder.This material was taken up in 300 mL of CH₂Cl₂ and treated with diluteaqueous NaHCO₃ solution. The aqueous phase was extracted with CH₂Cl₂(8×300 mL) until tlc analysis indicated complete extraction. Thecombined organic mixture was dried (Na₂SO₄), filtered, and concentratedin vacuo to provide the titled free amine as a pale brown oil.

Step F:1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)imidazolylmethyl]-2-piperazinoneDihydrochloride

To a solution of the amine from Step E (55.4 mmol, prepared above) in200 mL of 1,2-dichloroethane at 0° C. was added 4A powdered molecularsieves (10 g), followed by sodium triacetoxyborohydride (17.7 g, 83.3mmol). The imidazole carboxaldehyde from Step E of Example 4 (11.9 g,56.4 mmol) was added, and the reaction was stirred at 0° C. After 26hours, the reaction was poured into EtOAc, washed with dilute aq.NaHCO₃, and the aqueous layer was back-extracted with EtOAc. Thecombined organics were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting product was taken up in 500 mL of5:1 benzene:CH₂Cl₂, and propylamine (20 mL) was added. The mixture wasstirred for 12 hours, then concentrated in vacuo to afford a pale yellowfoam. This material was purified by silica gel chromatography (2-7%MeOH/CH₂Cl₂), and the resultant white foam was taken up in CH₂Cl₂ andtreated with 2.1 equivalents of 1 M HCl/ether solution. Afterconcentrated in vacuo, the product dihydrochloride was isolated as awhite powder.

Example 3 Preparation ofN-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine Methyl Ester(Compound 3-1)

Step A. Preparation ofN-(2(R)-t-butoxycarbonyl-amino-3-triphenyl-methylmercaptopropyl)-valyl-isoleucyl-leucineMethyl Ester

The tripeptide ester valyl-isoleucyl-leucine methyl ester wassynthesized using conventional solution phase peptide synthesis methods.The trifluoroacetate salt of this tripeptide (360 mg, 0.77 mmol) wasdissolved in 5 mL of methanol with 147 mg (1.5 mmol) of potassiumacetate and 670 mg (1.5 mmol) of N-Boc-S-tritylcysteinal (prepared usingthe procedure of Goel, Krolls, Stier, and Kesten Org. Syn. 67: 69-74(1988) for the preparation of N-Boc-leucinal) was added. Sodiumcyanoborohydride (47 mg, 0.75 mmol) was added and the mixture wasstirred overnight. The mixture was diluted with ether and washed withwater, 5% ammonium hydroxide and brine. The solution was dried (sodiumsulfate) and evaporated to give a white foam which was purified bychromatography (1-15% acetone in methylene chloride). The title compoundwas obtained as an oily material.

Step B. Preparation ofN-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine Methyl Ester

A sample of the protected pseudopeptide prepared as described in Step A(728 mg, 0.92 mmol) was dissolved in 100 mL of methylene chloride, 50 mLof TFA was added and the resulting yellow solution was treatedimmediately with 0.80 mL (5 mmol) of triethylsilane. After 45 min, thesolvents were evaporated and the residue was partitioned between hexaneand 0.1% aqueous TFA. The aqueous solution was lyophilized. Thismaterial was further purified by reverse phase HPLC (5-95%acetonitrile/0.1% TFA/water) to afford the title compound. ¹H NMR(CD₃OD) δ 8.65 (1H, d), 4.45 (1H, m), 4.3 (1H, d), 3.7 (3H, s), 3.4 (1H,m), 3.15 (1H, d), 2.75-2.95 (m), 0.8-1.05 (18H, m). FAB mass spectrum,m/z=447 (M+1).

Anal. Calcd for C₂₁H₄₂N₄O₄S.1.8 TFA: C, 45.24; H, 6.75; N, 8.56.

Found: C, 45.26; H, 6.77; N. 8.50.

Example 4 N-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine(Compound 7-2)

Step A. Preparation ofN-(2(R)-t-butoxycarbonylamino-3-triphenylmethylmercaptopropyl)-valyl-isoleucyl-leucine

The product of Example 3, Step A (60 mg, 0.076 mmol) was dissolved in 1mL of methanol and 150 μL of 1N NaOH was added. After stirringovernight, the solution was acidified with 150 μL of 10% citric acid andthe product was extracted with ether. The ether solution was washed withwater and brine and dried (sodium sulfate). Evaporation provided thetitle compound as a solid.

Step B. Preparation ofN-(2(R)-amino-3-mercaptopropyl)-valyl-isoleucyl-leucine

Using the method of Example 3, Step B, the protecting groups wereremoved with TFA and triethylsilane to provide the title compound. FABmass spectrum, m/z=433 (M+1).

Anal. Calcd for C₂₀H₄₀N₄O₄S.2 TFA: C, 43.63; H, 6.41; N, 8.48.

Found: C, 43.26; H, 6.60; N. 8.49.

Example 5 Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserineLactone (Compound 5-1) and2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-homoserine(Compound 5-2)

Step A: Preparation of N-(α-chloroacetyl)-L-isoleucinol

To a stirred solution of L-isoleucinol (20 g, 0.17 mol) andtriethylamine (28.56 ml, 0.204 mol) in CH₂Cl₂ (500 ml) at −78° C. wasadded chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. Thecooling bath was removed and the solution allowed to warm to −20° C. Themixture was diluted with EtOAc and washed sequentially with 1 M HCl, andbrine and dried (Na₂SO₄). Evaporation in vacuo afforded the amide titlecompound (35 g, 100%).

Rf=0.3 CH₂Cl₂: MeOH (95:5);

¹H NMR (CDCl₃) δ 6.80 (1H, brd, J=5 Hz), 4.10 (2H, s), 3.84 (1H, m),3.79 (2H, m), 2.65 (1H, brs), 1.72 (1H, m), 1.55 (1H, m), 1.17 (1H, m),0.96 (3H, d, J=6 Hz) 0.90 (3H, t, J=6 Hz).

Step B: Preparation of5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1.4-oxazin-3-one

To a stirred solution of N-(α-chloroacetyl)-L-isoleucinol (7.4 g, 0.038mol) in THF (125 ml) under argon at 0° C. was slowly added sodiumhydride (2.2 g of a 60% dispersion in mineral oil, 0.055 mol) withconcomitant gas evolution. After completing the addition, the mixturewas warmed to room temperature (R.T.) and stirred for 16 hr. Water (2.8ml) was added and the solvents evaporated in vacuo. The residue wasdissolved in CHCl₁₃ (70 ml) and washed with water saturated NaClsolution. The organic layer was dried (Na₂SO₄) and evaporated in vacuo.The residue was chromatographed using silica gel eluting withCH₂Cl₂:MeOH (96:4) to afford the lactam title compound (4.35 g, 72%) asa white solid.

Rf=0.35 CH₂Cl₂:MeOH (95:5);

¹H NMR δ (CDCl₃) 6.72 (1H, brs), 4.20 (1H, d, J=14.5 Hz), 4.10 (1H, d,J=14.5 Hz), 3.88 (1H, dd, J=9 and 3.5 Hz), 3.58 (1H, dd, J=9 and 6.5Hz), 3.45 (1H, brqt, J=3.5 Hz), 1.70-1.45 (2H, m), 1.34-1.15 (1H, m),0.96 (3H, t, J=6.5 Hz), 0.94 (3H, d, J=6.5 Hz).

Step C: Preparation ofN-(tert-butoxycarbonyl)-5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one

5(S)-[1(S)-Methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one (12.2 g,0.0776 mol) and DMAP (18.9 g, 0.155 mol) were dissolved in methylenechloride (120 ml) under argon at R.T. Boc anhydride (33.9 g, 0.155 mol)was added to the stirred solution in one portion, with concomitant gasevolution and the mixture was stirred at R.T. for 16 hr. The solvent wasevaporated in vacuo and the residue was taken up in ethyl acetate andwashed sequentially with 10% citric acid, 50% NaHCO₃ and finally brine.The organic extract was dried (Na₂SO₄) and evaporated in vacuo.Chromatography of the residue over silica gel eluting with 20% EtOAc inhexanes afforded the title compound (14.1 g, 71%) as a white solid.

Rf=0.75 EtOAc:hexanes (20:80); mp 59-60° C.

Anal. Calc'd. for Cl₃H₂₃O₄N: C, 60.68; H, 9.01; N, 5.44.

Found: C, 60.75; H, 9.01; N, 5.58.

¹H NMR (CDCl₃) δ 4.25 (1H, d, J=15 Hz), 4.15 (1H, d, J=15 Hz), 4.15-4.00(2H, m), 3.73 (1H, dd, J=10 and 2 Hz), 1.88 (1H, qt, J=6 Hz), 1.55 (9H,s), 1.50-1.36 (1H, m), 1.35-1.19 (1H, m) 1.00 (3H, d, J=6 Hz) 0.95 (3H,d, J=6.5 Hz).

Step D: Preparation ofN-(tert-Butoxycarbonyl)-2(S)-benzyl-5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one

A solution ofN-(tert-butoxycarbonyl)-5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one(5.75 g, 22.34 mmol) in DMF (100 ml) under argon was cooled to −60° C.The cold solution was transferred via canula to a second flaskcontaining sodium bis(trimethylsilyl)amide (24.58 ml of a 1M solution inTHF, 24.58 mmol) at −78° C. under argon. After stirring for 10 minutes,benzyl bromide (2.25 ml, 18.99 mmol) was added over 5 minutes and theresulting mixture was stirred at −78° C. for 3 hours. After this time,the reaction mixture was transferred via cannula to another flaskcontaining sodium bis(trimethylsilyl)amide (24.58 ml of a 1M solution inTHF, 24.58 mmol) at −78° C., under argon. After stirring for a further 5minutes, the reaction was quenched by the addition of saturated aqueousammonium chloride solution (24.6 ml) and allowed to warm to roomtemperature. This mixture was diluted with brine (50 ml) and water (20ml) and then extracted with ethyl acetate (2×100 ml). The organicextracts were washed with brine (50 ml) and evaporated in vacuo toafford an oil. Chromatography of the residue over silica gel (230-400mesh, 300 g) eluting with 10-20% ethyl acetate in hexanes afforded thetitle compound (5.12 g, 67%) as a clear oil.

Rf=0.25 EtOAc:Hexanes (20:80);

¹H NMR (CDCl₃) δ 7.35-7.15 (5H, m), 4.31 (1H, dd, J=6 and 2 Hz), 4.03(1H, d, J=12 Hz), 3.88 (1H, dd, J=6 and 1 Hz), 3.66 (1H, dd, J=12 and 2Hz), 3.29 (1H, dd, J=12 and 3 Hz), 1.54 (9H, s), 3.12 (1H, dd, J=12 and7 Hz), 1.47 (1H, m), 1.25 (1H, m), 1.10 (1H, m), 0.83 (3H, d, J=6 Hz),0.80 (3H, t, J=6 Hz).

Step E: Preparation ofN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenyl-propionicAcid

To a stirred solution ofN-(tert-butoxycarbonyl)-2(S)-benzyl-5(S)-[1(S)-methyl]-propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one(5.1 g, 14.7 mmol) in THF (150 ml) and water (50 ml) at 0° C. was addedhydrogen peroxide (15 ml of a 30% aqueous solution, 132 mmol) andlithium hydroxide (3.0 g, 63.9 mmol). After stirring for 30 minutes, thereaction was quenched with a solution of sodium sulfite (28.25 g, 0.224mol) in water (70 ml). The THF was evaporated in vacuo and the aqueousphase was acidified to pH 3-4 by addition of 10% citric acid solutionand extracted with EtOAc. The organic extracts ere dried (Na₂SO₄),evaporated in vacuo and the residue purified by chromatography oversilica gel eluting with 4% MeOH in CH₂Cl₂ to give the lactam2(S)-benzyl-5(S)-[1(S)-methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one(0.82 g 22%) and then with 20% MeOH in CH₂Cl₂ to afford the titlecompound (4.03 g, 75%) as a viscous oil.

Rf=0.4 MeOH:CH₂Cl₂ (5:95)+0.3% AcOH;

¹H NMR (d₆ DMSO) δ 7.35-7.10 (5H, m), 6.68 (1H, br, s), 3.75 (1H, dd,J=7.5 and 2.5 Hz) 3.54 (1H, m), 3.5-3.2 (2H, m) 2.99 (1H, dd, J=12.5 and2.5 Hz), 2.75 (1H, dd, J=12.5 and 7.5 Hz), 1.50-1.35 (11H, m), 0.98 (1H,sept, J=6 Hz), 0.78 (3H, t, J=6 Hz), 0.65 (3H, d, J=6 Hz);

FAB MS 366 (MH⁺) 266 (MH₂ ⁺—CO₂tBu).

Step F: Preparation ofN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenyl-propionyl-homoserineLactone

To a stirred solution ofN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionicacid (0.53 g, 1.45 mmol) and 3-hydroxy-1,2,3,-benzotriazin-4(3H)-one(HOOBT) (0.26 g, 1.6 mmol) in DMF (15 ml) at room temperature was addedEDC (0.307 g, 1.6 mmol) and L-homoserine lactone hydrochloride (0.219 g,6.0 mmol). The pH was adjusted to pH=6.5 by addition of NEt₃ (the pH wasmonitored by application of an aliquot of the reaction mixture to amoist strip of pH paper). After stirring at room temperature for 16 hr,the reaction was diluted with EtOAc and washed with saturated NaHCO₃ andthen brine and dried (NaSO₄). Evaporation in vacuo (sufficient to removeDMF) and chromatography over silica gel eluting with 5% acetone inCH₂Cl₂ afforded the title compound (520 mg, 80%) as a white solid, mp115-117° C.

Rf=0.3 Acetone: CH₂Cl₂ (5:95).

¹H NMR (CDCl₃) δ 7.73 (1H, brd, J=5 Hz), 7.40-7.15 (5H, m), 4.68 (1H,dt, J=9 and 7.5 Hz), 4.65-4.35 (2H, m), 4.33-4.18 (1H, m), 4.20 (1H, dd,J=7 and 3 Hz), 3.78 (1H, m), 3.49 (1H, dd, J=7.5 and 4.0 Hz), 3.37 (1H,dd, J=7.5 and 6.5 Hz), 3.15 (1H, dd, J=11.5 and 2 Hz), 2.86 (1H, dd,J=11.5 and 7.5 Hz), 2.68 (1H, m) 2.11 (1H, q, J=9 Hz), 1.55-1.30 (11H,m), 1.07 (1H, m), 0.87 (3H, t, J=6.3 Hz), 0.79 (3H, d, J=6 Hz).

Step G: Preparation of2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserineLactone Hydrochloride

Anhydrous HCl gas was bubbled through a cold (0° C.) solution ofN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserinelactone (3.0 g, 6.7 mmol) in ethyl acetate (120 ml) until a saturatedsolution was obtained. The resulting mixture was stirred at 0° C. for 1hr. The solution was purged with nitrogen and the mixture concentratedin vacuo to afford the title compound as a sticky foam which was usedwithout further purification.

¹H NMR (d₆ DMSO) δ 8.60 (1H, d, J=7 Hz), 8.08 (3H, brs), 7.35-7.15 (5H,m), 4.60 (1H, qt, J=8 Hz), 4.36 (1H, t J=7.5 Hz), 4.22 (1H, q, J=7.5Hz), 4.15-3.95 (2H, m), 3.64 (1H, dd, J=9 and 2.5 Hz), 3.15-3.00 (2H,m), 2.92 (1H, dd, J=12.5 and 5.0 Hz), 2.40-2.15 (2H, m), 1.65 (1H, m),1.43 (1H, m), 1.07 (1H, m), 0.82 (3H, t, J=6 Hz), 0.72 (3H, d, J=6.0Hz).

Step H: Preparation of2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserineLactone

2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-homoserinehydrochloride (6.7 mmol) andN-(tert-butoxy-carbonyl)-S-triphenylmethylcysteine aldehyde (0.74 g, 7.5mmol) (prepared from N-(tert-butoxycarbonyl)-S-triphenylmethylcysteineby the procedure of Goel, O. P.; Krolls, U.; Stier, M.; Keston, S. Org.Syn. 1988, 67, 69.) and potassium acetate (3.66 g, 8.2 mmol) weredissolved in methanol (48 ml). Activated 4A molecular sieves (6 g) andthen Na(CN)BH₃ (0.70 g, 10.7 mmol) were added and the resulting slurrywas stirred under argon at room temperature for 16 hr. The solids wereremoved by filtration and the filtrate evaporated in vacuo. The residuewas dissolved in EtOAc and washed sequentially with saturated aqueousNaHCO₃ and brine and then dried (Na₂SO₄). Evaporation in vacuo affordedan oil which was purified by chromatography over silica gel eluting witha gradient of 30-50% EtOAc in hexane to afford the title compound (2.34g, 45%) contaminated with a small amount of the corresponding methylester.

¹H NMR (CD₃OD) δ 7.60-7.05(20H, m), 4.64 (1H, d, J=9.0 Hz), 4.39 (1H, brt, J=9 Hz), 4.25(1H, m), 3.93 (1H, m), 3.75-3.60(1H, m), 3.55 (1H, dd,J=9.0 and 2 Hz), 3.20 (1H, dd, J=9.0 and 6.0 Hz), 3.04 (1H, dd, J=15.0and 5.0 Hz), 2.85 (1H, dd, J=15.0 and 9.0 Hz), 2.60 (1H, dd, J=12.0 and5.0 Hz), 2.50-2.15 (7H, m), 1.45 (9H, s), 1.40-1.20 (1H, m), 1.07 (1H,m), 0.87 (3H, t, J=6 Hz), 0.67 (3H, d, J=6.0 Hz).

Step I: Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserineLactone

To a stirred solution of2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserinelactone (2.72 g, 3.49 mmol) in CH₂Cl₂ (90 ml) was added HSiEt₃ (2.16 ml,13.5 mmol) and TFA (43.2 ml, 0.56 mol) and the solution was stirred atR.T. under argon for 2 hrs. The solvent was evaporated in vacuo and theresidue partitioned between 0.1% aqueous TFA (200 ml) and hexanes (100ml). The aqueous layer was separated and washed with hexanes (20 ml) andthen lyophilised. The resulting white lyophilate was chromatographed in5 equal portions over a Waters Prepak cartridge (C-18, 15-20 mM 100 A)eluting with a gradient of 95:5 to 5:95 0.1% TFA in H₂O :0.1% TFA inCH₃CN at 100 ml/min over 60 min. The desired compound eluted after 19min. The CH₃CN was evaporated in vacuo and the aqueous solutionlyophilised to afford the title compound (1.95 g, 77%) as the TFA salt.

The salt is hygroscopic and is prone to disulphide formation if left insolution and exposed to air.

¹H NMR δ (CD₃OD) 7.40-7.15 (5H, m), 4.55-5.40 (2H, m), 4.33 (1H, m),4.18 (1H, m), 3.90-3.62 (3H, m), 3.53 (1H, dd, J=10.5 and 4.0 Hz), 3.37(1H, dd, J=10.5 and 6.0 Hz), 3.23 (1H, m), 3.15-2.95 (2H, m), 2.88 (1H,dd, J=12.5 and 5.0 Hz), 2.55-2.25 (2H, m), 1.92 (1H, m), 1.49 (1H, m),1.23 (1H, m), 0.94 (3H, t, J=6 Hz), 0.90 (3H, d, J=6 Hz).

FAB MS 873 (2M−H⁺) 438 (MH⁺) 361 (MH±Ph)

Anal. calc'd for C₂₂H₃₆O₄N₃S₂.6 TFA: C, 43.58; H, 5.25; N, 5,82.

Found: C, 43.62; H, 5.07; N, 5.80.

Step J: Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine

2(S)-[2(S)-[2(R)-Amino-3-mercapto]propyl-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserinelactone (0.00326 mmol) was dissolved in methanol (0.0506 ml) and 1Nsodium hydroxide (0.0134 ml) was added followed by methanol (0.262 ml).The conversion of the lactone to the hydroxy-acid was confirmed by HPLCanalysis and NMR.

Example 6 Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine

Step A: Preparation of2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methionine

To a solution of2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninemethyl ester (120 mg, 0.143 mmol) in methanol (4 ml) was added sodiumhydroxide (1N, 0.57 ml, 0.57 mmol) and the resulting mixture was stirredat room temperature for 3 hours. Another portion of sodium hydroxide(1N, 0.25 ml) was added and stirring continued for 0.5 hours. Thereaction mixture was concentrated and the residue was dissolved in aminimum amount of water and neutralized with hydrochloric acid (1N, 0.87ml). The aqueous solution was extracted with ethyl acetate three times.The combined extracts were dried (Na₂SO₄) and concentrated to yield thetitle compound (110 mg, 0.133 mmol, 93%). NMR (CD₃OD) 60.70 (3H, d, J=6Hz), 0.80 (3H, t, J=6 Hz), 1.05 (H, m), 1.34 (9H, s), 1.60 (H, m), 1.95(3H, S), 2.7˜2.9 (3H, m), 2.95˜3.1 (2H, m), 3.95 (H, d of d, J=8.4 Hz),4.27 (H, d of d, J=8.6 Hz), 7.1˜7.4 (20H, m).

Step B: Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine

The title compound was prepared in the same manner as that described inExample 5, Step I, but using2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninein place of2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserinelactone. NMR (CD₃OD) δ 0.82 (3H, d, J=6 Hz), 0.95 (3H, t, J=6 Hz), 1.20(H, m), 1.40 (H, m), 1.85 (H, m), 2.10 (3H, s), 2.4˜2.6 (2H, m), 3.1˜3.2(2H, m), 3.35 (H, d of d, J=14, 6 Hz), 3.55 (H, d of d, J=14, 5 Hz),4.20 (H, d of d, J=10, 5 Hz), 4.63 (H, d of d, J=10.6 Hz), 7.27 (5H, m).

Anal. Calcd for C₂₃H₃₉N₃O₄S₂.2CF₃CO₂H.2H₂O: C, 43.25; H, 6.05; N, 5.60.

Found: C, 43.09; H, 6.01; N, 5.46.

Example 7 Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionineSulfone Methyl Ester (Compound 7-1)

Step A: Preparation of Methionine Sulfone Methyl Ester

Thionyl chloride (2.63 ml, 36 mmol) was added dropwise to a stirredsolution of N-Boc-Met sulfone (5 g, 18 mmol) in methanol (40 ml) cooledat 0° C. After the completion of the addition, the resulting mixture waswarmed to room temperature and stirred overnight. The reaction mixturewas recooled to 0° C. and slowly treated with solid sodium bicarbonateto adjust the pH to 7. The mixture was concentrated in vacuo to removemethanol and the residue was dissolved in a minimum amount of water(solution pH ca. 10) and extracted with ethyl acetate four times. Thecombined extracts were dried (Na₂SO₄) and concentrated to give the titlecompound (1.5 g). NMR (CD₃OD) δ 2.04 (H, m), 2.21 (H, m), 2.98 (3H, s),3.23 (2H, t, J=7 Hz), 3.63 (H, d of d, J=8.6 Hz), 3.77 (3H, s).

Step B: Preparation ofN-(tert-Butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3-phenyl-propionyl-methionineSulfone Methyl Ester

The title compound was prepared in the same fashion as that described inExample 8, Step F, but using methionine sulfone methyl ester in place ofhomoserine lactone hydrochloride. NMR (CD₃OD) δ 0.80 (3H, d, J=6 Hz),0.88 (3H, t, J=6 Hz), 1.12 (H, m), 1.47 (9H, s), 2.10 (H, m), 2.32 (H,m), 2.93 (3H, s), 3.5˜3.7 (2H, m), 3.74 (3H, s), 4.01 (H, d of d, J=7.4Hz), 4.60 (H, d of d, J=9.5 Hz), 6.60 (H, d, J=8 Hz), 7.25 (5H, m).

Step C: Preparation of2(S)-[2(S)-Amino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionineSulfone Methyl Ester Hydrochloride

The title compound was prepared in the same fashion as that described inExample 5, Step G, but usingN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methioninesulfone methyl ester in place ofN-(tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine lactone. NMR (CD₃OD) δ0.85 (3H, d, J=6 Hz), 0.94 (3H, t, J=6 Hz), 1.20 (H, m), 1.52 (H, m),1.72 (H, m), 2.14 (H, m), 2.38 (H, m), 2.98 (3H, s), 3.57 (H, d of d,J=12, 6 Hz), 3.73 (H, d of d, J=12, 9 Hz), 3.78 (3H, s), 4.15 (H, d ofd, J=8.6 Hz), 4.63 (H, d of d, J=8.5 Hz), 7.30 (5H, m).

Step D: Preparation of2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methionineSulfone Methyl Ester

The title compound was prepared in a similar fashion as that describedin Example 5, Step H, but using2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methioninesulfone methyl ester hydrochloride in place of2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserinelactone hydrochloride. NMR (CD₃OD) δ 0.70 (3H, d, J=6 Hz), 0.88 (3H, t,J=6 Hz), 1.10 (H, m), 1.47 (9H, s), 2.15 (H, m), 2.67 (H, m), 2.92 (3H,s), 3.67 (H, m), 4.68 (H, d of d, J=10, 6 Hz), 7.15˜7.45 (20H, m).

Step E: Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionineSulfone Methyl Ester

The title compound was prepared in a similar fashion as that describedin Example 5, Step I, but using2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone methyl ester in place of2(S)-[2(S)-[2(R)-(tert-butoxy-carbonyl)-amino-3-triphenylmethylmercapto]propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-homoserinelactone. NMR (CD₃OD) δ 0.83 (3H, d, J=6 Hz), 0.93 (3H, t, J=6 Hz), 1.20(H, m), 1.51 (H, m), 1.80 (H, m), 2.22 (H, m), 2.43 (H, m), 3.00 (3H,s), 3.78 (3H, s), 4.20 (H, d of d, J=8.4 Hz), 4.72 (H, d of d, J=10, 6Hz), 7.30 (5H, m).

FABMS m/z 532 (MH⁺).

Example 8 Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionineSulfone (Compound 8-1)

Step A: Preparation of2(S)-[2(S)-[2(R)-(tert-Butoxy-carbonyl)-amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]pentyloxy-3-phenyl-propionyl-methionineSulfone

The title compound was prepared in a similar fashion as that describedin Example 6, Step A, but using2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone methyl ester in place of2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylmercapto]propylamino-3(S)-methyl]pentyloxy-methioninemethyl ester. NMR (CD₃OD) δ 0.79 (3H, d, J=6 Hz), 0.90 (3H, t, J=6 Hz),1.47 (9H, s), 2.92 (3H, s), 4.08 (H, m), 4.32 (H, m), 7.15˜7.35 (20H,m).

Step B: Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionineSulfone

The title compound was prepared in a similar fashion as that describedin Example 5, Step I, but using2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-triphenylmethylmercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone in place of2(S)-[2(S)-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethyl-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserinelactone. NMR (CD₃OD) δ 0.84 (3H, d, J=6 Hz), 0.94 (3H, t, J=6 Hz), 1.21(H, m), 1.50 (H, m), 1.82 (H, m), 2.24 (H, m), 2.47 (H, m), 2.98 (3H,s), 3.6˜3.75 (3H, m), 4.20 (H, d of d, J=9.5 Hz), 4.64 (H, d of d, J=9.6Hz), 7.30 (5H, m).

Anal. Calcd for C₂₃H₃₉N₃O₆S₂.3CF₃CO₂H: C, 40.51; H, 4.92; N, 4.89.

Found: C, 40.47; H, 5.11; N, 4.56.

Example 9 Preparation of2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionineSulfone Isopropyl Ester (Compound A)

The title compound was prepared using methods A-E from Example 7, exceptfor Method A. Methionine sulfone isopropyl ester was prepared bycoupling t-butyloxycarbonyl-methionine sulfone with isopropyl alcoholusing dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP)followed by deprotection with HCl in EtOAc. NMR (CD₃OD) δ 0.83 (3H, d,J=6 Hz), 0.94 (3H, t, J=6 Hz), 1.11-1.56 (2H, m), 1.28 (6H, d, J=6 Hz),1.8-1.96 (1H, m), 2.12-2.27 (1H, m), 2.89-3.0 (2H, m), 3.01 (3H, s),3.06-3.3 (4H, m), 3.42 (1H, dd, J=6, 13 Hz), 3.65 (1H, dd, J=6, 13 Hz),3.68-3.91 (3H, m), 4.2-4.27 (1H, m), 4.61-4.7 (1H, m), 4.96-5.12 (2H,m), 7.19-7.44 (5H, m).

Anal. Calc'd. for C₂₆H₄₅N₃O₆S₂.2CF₃CO₂H: C, 44.07; H, 5.67; N, 4.97;

Found: C, 44.35; H, 5.68; N, 5.23

Example 104-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile

Step 1: 5-Chloro-5′-methyl-[1,2′]bipyridinyl-2-one

5-Chloro-2-pyridinol (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K₂CO₃ (2.66 g, 19.2 mmol)were heated at 180° C. for 16 hrs. The brown reaction mixture wascooled, diluted with EtOAc and washed with saturated NaHCO₃. The aqueouslayer was extracted with EtOAc (2×) and the combined organic extractswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresidue was chromatographed (silica gel, EtOAc: CH₂Cl₂ 20:80 to 50:50gradient elution) to afford the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.65 (dd, J=2.4 and 8.2 Hz, 1H), 7.32 (dd, J=2.9 and 9.7Hz, 1H), 6.61 (d, J=9.7 Hz, 1H) and 2.39 (s, 3H) ppm.

Step 2: 5′-Bromomethyl-5-chloro-[1,2′]bipyridinyl-2-one

A solution of the pyridine from Step 1 (1.00 g, 4.53 mmol),N-bromosuccinimide (0.81 g, 4.53 mmol) and AIBN (0.030 g, 0.18 mmol) inCCl₄ (40 mL) was heated at reflux for 2 hrs. The solids were filteredand the filtrate collected. The solvent was evaporated in vacuo and theresidue chromatographed (silica gel, EtOAc:CH₂Cl₂ 25:75 to 50:50gradient elution) to afford the title bromide.

¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.04 (d, J=2.9 Hz, 1H), 8.01 (d,J=8.4 Hz, 1H), 7.88 (dd, J=2.4 and 8.6 Hz, 1H), 7.34 (dd, J=2.9 and 9.8Hz, 1H), 6.61 (d, J=9.9 Hz, 1H) and 4.51 (s, 2H) ppm.

Step 3:4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrileHydrochloride

The bromide from Step 2 (0.750 g, 2.50 mmol) and the4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (1.06 g, 2.50 mmol) inCH₃CN (10 mL) were heated at 60° C. The reaction was cooled to roomtemperature and the solids collected by filtration and washed with EtOAc(10 mL). The solid was suspended in methanol (50 mL) and heated atreflux for 1 hr, cooled and the solvent evaporated in vacuo. The stickyresidue was stirred in EtOAc (40 mL) for 4 hrs and the resulting solidhydrobromide salt collected by filtration and washed with EtOAc (40 mL)and dried in vacuo. The hydrobromide salt was partitioned between sat.NaHCO₃ and CH₂Cl₂ and extracted with CH₂Cl₂. The organic extracts weredried (Na₂SO₄) and evaporated in vacuo. The residue was chromatographed(silica gel, MeOH:CH₂Cl₂ 4:96 to 5:95 gradient elution) to afford thefree base which was converted to the hydrochloride salt to afford thetitle compound as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.35 (s, 1H), 8.03 (d, J=2.9 Hz,1H), 7.83 (d, J=8.4 Hz, 1H), 7.76 (dd, J=2.4 and 9.6 Hz, 1H), 7.68-7.58(m, 3H), 7.48 (s, 1H), 7.31 (d, J=8.6 Hz, 2H), 6.68 (d, J=9.3 Hz, 1H),5.53 (s, 2H) and 4.24 (s, 2H) ppm.

Analysis: Calc for C₂₂H₁₆N₅OCl: 1.75 HCl, 0.15 EtOAc C 56.69, H 3.99, N14.62

Found: C 56.72, H 4.05, N 14.54

Example 11 Preparation of(R)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinoneDihydrochloride

Step A: Preparation of(R)-2-(tert-butoxycarbonylamino)-N-(3-chlorophenyl)-3-[(triphenylmethyl)thio]-1-propanamine

To a solution of 3-chloroaniline (0.709 mL, 6.70 mmol) in 30 mL ofdichloromethane at room temperature was added 1.2 g of crushed 4 Åmolecular sieves. Sodium triacetoxyborohydride (3.55 g, 16.7 mmol) wasadded, followed by dropwise addition of N-methylmorpholine to achieve apH of 6.5. L-S-Trityl-N-Boc-cysteinal (3.15 g, 7.04 mmol) (preparedaccording to S. L. Graham et al. J. Med. Chem., (1994) Vol. 37, 725-732)was added, and the solution was stirred for 48 hours. The reaction wasquenched with sat. aq. NaHCO₃, diluted with EtOAc, and the layers wereseparated. The organic material was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to provide an oil which was purifiedby silica gel chromatography (15% EtOAc/hexane) to give the title amine.

Step B: Preparation of(R)-N-[2-(tert-butoxycarbonylamino)-3-((triphenylmethyl)thio)propyl]-2-chloro-N-(3-chlorophenyl)acetamide

The aniline derivative from Step A (2.77 g, 4.95 mmol) was dissolved in73 mL of EtOAc and 73 mL of sat. NaHCO₃ soln., then cooled to 0° C. Withvigorous stirring, chloroacetyl chloride (0.533 mL, 6.69 mmol) was addeddropwise. After 3 hours, the reaction was diluted with water and EtOAc,and the organic layer was washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to provide crude titled chloroacetamide whichwas used without further purification.

Step C: Preparation of(R)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[S-(triphenylmethyl)thiomethyl]piperazin-2-one

To a solution of chloroacetamide from Step B (3.29 g crude,theoretically 4.95 mmol) in 53 mL of DMF at 0° C. was added cesiumcarbonate (4.84 g, 14.85 mmol). The solution was stirred for 48 hours,allowing it to warm to room temperature. The solution was poured intoEtOAc, washed with water and brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to provide the crude product as an oil. Thismaterial was purified by silica gel chromatography (20% EtOAc/hexane) toyield the product as a white solid.

Step D: Preparation of(R)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-(thiomethyl)piperazin-2-one

A solution of piperazinone from Step C (625 mg, 1.04 mmol) in degassedEtOAc (38 mL) and EtOH (12 mL) was warmed to 30° C. A solution of AgNO₃(177 mg, 1.04 mmol) and pyridine (0.084 mL, 1.04 mmol) in 8 mL of EtOHwas added, and the solution was heated to reflux. After 45 minutes, thereaction was concentrated in vacuo, then redissolved in 26 mL ofdegassed EtOAc. Through this solution was bubbled H₂S gas for 2.5minutes, then activated charcoal was added after 4 minutes. The materialwas filtered through celite and rinsed with degassed EtOAc, concentratedin vacuo, then reconcentrated from degassed CH₂Cl₂ to provide the crudeproduct which was used without further purification.

Step E: Preparation of(R)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[(ethylthio)methyl]piperazin-2-one

A solution of the thiol from Step D (ca. 1.04 mmol) in 3 mL of THF wasadded via cannula to a suspension of NaH (51.4 mg, 60% disp. in mineraloil, 1.28 mmol) in 2 mL THF at 0° C. After 10 minutes, iodoethane wasadded (0.079 mL, 0.988 mmol), and the solution was stirred for 1.5hours. The reaction was poured into EtOAc, washed with sat. NaHCO₃ andbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to providethe crude product. This material was purified by silica gelchromatography (1% MeOH/CH₂Cl₂) to yield the titled product.

Step F: Preparation of(R)-4-(tert-butoxycarbonyl)-1-(3-chlorophenyl)-5-[(ethanesulfonyl)methyl]piperazin-2-one

To a solution of the sulfide from Step E (217 mg, 0.563 mmol) in 3 mL ofMeOH at 0° C. was added a solution of magnesium monoperoxyphthalate (835mg, 1.69 mmol) in 2 mL MeOH. The reaction was stirred overnight,allowing it to warm to room temperature. The solution was cooled to 0°C., quenched by the addition of 4 mL 2N Na₂S₂O₃ soln., then concentratedin vacuo. The residue was partitioned between EtOAc and sat NaHCO₃solution, and the organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to provide the crude sulfone as awhite waxy solid.

Step G: Preparation of(R)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinoneDihydrochloride

To a solution of the Boc-protected piperazinone from Step F (224 mg,0.538 mmol) in 5 mL of dichloromethane at 0° C, was added 2.5 mL oftrifluoroacetic acid (TFA). After 45 minutes, the reaction wasconcentrated in vacuo, then azeotroped with benzene to remove the excessTFA. The residue was taken up in 4 mL of 1,2-dichloroethane and cooledto 0° C. To this solution was added 4 Å powdered molecular sieves (340mg), followed by sodium triacetoxyborohydride (285 mg, 1.34 mmol) andseveral drops of triethylamine to achieve pH=6. The imidazolecarboxaldehyde from Step E of Example 42 (125 mg, 0.592 mmol) was added,and the reaction was stirred at 0° C. After 2 days, the reaction waspoured into EtOAc, washed with dilute aq. NaHCO₃, and brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude product wastaken up in methanol and injected onto a preparative HPLC column andpurified with a mixed gradient of 15%-50% acetonitrile/0.1% TFA; 85%-50%0.1% aqueous TFA over 60 minutes. After concentration in vacuo, theresultant product was partitioned between dichloromethane and aq. NaHCO₃soln., and the aqueous phase was extracted with CH₂Cl₂. The organicsolution was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to dryness to provide the product free base, which wastaken up in CH₂Cl₂ and treated with 2.1 equivalents of 1 M HCl/ethersolution. After concentrated in vacuo, the product dihydrochloride wasisolated as a white powder.

BIOLOGICAL ASSAYS

The ability of compounds of the present invention to inhibit cancer canbe demonstrated using the following assays.

In Vitro Inhibition of Farnesyl-Protein Transferase

Transferase Assays.

Isoprenyl-protein transferase activity assays were carried out at 30° C.unless noted otherwise. A typical reaction contained (in a final volumeof 50 μL): [³H]farnesyl diphosphate or [³H]geranylgeranyl diphosphate,Ras protein, 50 mM HEPES, pH 7.5, 5 mM MgCl₂, 5 mM dithiothreitol andisoprenyl-protein transferase. The FPTase employed in the assay wasprepared by recombinant expression as described in Omer, C. A., Kral, A.M., Diehl, R. E., Prendergast, G. C., Powers, S., Allen, C. M., Gibbs,J. B. and Kohl, N. E. (1993) Biochemistry 32:5167-5176. Thegeranylgeranyl-protein transferase-type I employed in the assay wasprepared as described in U.S. Pat. No. 5,470,832, incorporated byreference. After thermally pre-equilibrating the assay mixture in theabsence of enzyme, reactions were initiated by the addition ofisoprenyl-protein transferase and stopped at timed intervals (typically15 min) by the addition of 1 M HCl in ethanol (1 mL). The quenchedreactions were allowed to stand for 15 m (to complete the precipitationprocess). After adding 2 mL of 100% ethanol, the reactions werevacuum-filtered through Whatman GF/C filters. Filters were washed fourtimes with 2 mL aliquots of 100% ethanol, mixed with scintillation fluid(10 mL) and then counted in a Beckman LS3801 scintillation counter.

For inhibition studies, assays were run as described above, exceptinhibitors were prepared as concentrated solutions in 100% dimethylsulfoxide and then diluted 20-fold into the enzyme assay mixture. IC₅₀values were determined with both transferase substrates near K_(M)concentrations. Nonsaturating substrate conditions for inhibitor IC₅₀determinations were as follows: FTase, 650 nM Ras-CVLS, 100 nM farnesyldiphosphate; GGPTase-I, 500 nM Ras-CAIL, 100 nM geranylgeranyldiphosphate.

In Vivo ras Prenylation Assay

The cell lines used in this assay consist of either Rat1 or NIH3T3 cellstransformed by either viral Ha-ras; an N-ras chimeric gene in which theC-terminal hypervariable region of v-Ha-ras was substituted with thecorresponding region from the N-ras gene; or ras-CVLL, a v-Ha-ras mutantin which the C-terminal exon encodes leucine instead of serine, makingthe encoded protein a substrate for geranylgeranylation by GGPTase I.The assay can also be performed using cell lines transformed with humanHa-ras, N-ras or Ki4B-ras. The assay is performed essentially asdescribed in DeClue, J. E. et al., Cancer Research 51:712-717, (1991).Cells in 10 cm dishes at 50-75% confluency are treated with the testcompound(s) (final concentration of solvent, methanol or dimethylsulfoxide, is 0.1%). After 4 hours at 37° C., the cells are labelled in3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetalbovine serum, 400 μCi[³⁵S]methionine (1000 Ci/mmol) and testcompound(s). Cells treated with lovastatin, a compound that blocks Rasprocessing in cells by inhibiting the rate-limiting step in theisoprenoid biosynthetic pathway (Hancock, J. F. et al. Cell, 57:1167(1989); DeClue, J. E. et al. Cancer Res., 51:712 (1991); Sinensky, M. etal. J. Biol. Chem., 265:19937 (1990)), serve as a positive control inthis assay. After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂/1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min.Alternatively, four hours after the addition of the labelling media, themedia is removed, the cells washed, and 3 ml of media containing thesame or a different test compound added. Following an additional 16 hourincubation, the lysis is carried out as above. Aliquots of lysatescontaining equal numbers of acid-precipitable counts are bought to 1 mlwith IP buffer (lysis buffer lacking DTT) and immunoprecipitated withthe ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al., J.Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C., 200 μl of a 25% suspension of protein A-Sepharose coated with rabbitanti rat IgG is added for 45 min. The immunoprecipitates are washed fourtimes with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-100.0.5%deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer andloaded on 13% acrylamide gels. When the dye front reached the bottom,the gel is fixed, soaked in Enlightening, dried and auto-radiographed.The intensities of the bands corresponding to prenylated andnonprenylated Ras proteins are compared to determine the percentinhibition of prenyl transfer to protein.

In Vivo Growth Inhibition of Ras Transformed Cells Assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cell lines transformed withhuman Ha-ras, N-ras or Ki4B-ras can also be utilized. Cells transformedby v-Raf and v-Mos may be included in the analysis to evaluate thespecificity of instant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photo-micrographs are takenapproximately 16 days after the cultures are seeded and comparisons aremade.

In addition, the activity of the compounds of the present invention fortreating cancer and/or inhibiting tumor growth is confirmed utilizingthe nude mouse tumor xenograft assay described in Kohl et al., PNAS 91(1994) 9141-45.

In Vitro Growth Inhibition of Human Tumor Cells Assays

Cancer cells (MCF-7, MDA-468, T47D, MDA-231, SkOv3, A549, SkBr3, PC3,LNCaP or DU-145) are seeded in 6 well clusters at 10,000 or 20,000 cellsper well. The growth media utilized in the cell assays is RPMI media[GIBCO], supplemented with 5 or 10% fetal calf serum, glutamine,penicillin and streptomycin. The cell are then treated under one of thefollowing protocols:

Protocol A

After one day in growth media, the cells are exposed to variousconcentrations of an antineoplastic agent for a four (4) hour period.The cells are then washed twice and placed in a growth media containinga farnesyl-protein transferase inhibitor (FTI) and incubated for 7 to 10days. At the end of the incubation the cells are harvested bytripsinization and counted in a Coulter counter.

Protocol B

The cells are placed in growth media containing a farnesyl-proteintransferase inhibitor (FTI). After one day in the FTI containing growthmedia, the cells are exposed to various concentrations of aantineoplastic agent for a four (4) hour period. The cells are thenwashed twice and again placed in a growth media containing afarnesyl-protein transferase inhibitor (FTI) and incubated for 7 to 10days. At the end of the incubation the cells are harvested bytripsinization and counted in a Coulter counter.

Protocol C

The cells are placed in growth media containing a farnesyl-proteintransferase inhibitor (FTI) and various concentrations of aantineoplastic agent. The cells are incubated for 7 to 10 days. At theend of the incubation the cells are harvested by tripsinization andcounted in a Coulter counter.

Protocol D-1

The cells are placed in growth media containing a antineoplastic agentat various concentrations for four (4) hours. The monolayer of cells isthen separated from the media and washed 4 tines with PBS. The cells aretrypsinized and counted with a Coulter counter. 20,000 cells arereplated on 6 well plates in 0.35% agar over a 0.7% agar layer, bothlayers which contain vehicle only, 0.2 μM, 2 μM or 20 μM of afarnesyl-protein transferase inhibitor. The cells are fed and treatedwith the FTI, or vehicle only, twice weekly. At the end of twelve daysincubation the cells are scored manually from duplicate wells.

Protocol D-2

The cells are placed in growth media containing a antineoplastic agentfor four (4) hours. The monolayer of cells is then separated from themedia and washed 4 times with PBS. The cells are trypsinized and countedwith a Coulter counter. 10,000 cells are replated on 12 well plates inthe standard RPMI media described above which contain vehicle only, 0.2μM or 2 μM of a farnesyl-protein transferase inhibitor. The cells arefed and treated with the FTI, or vehicle only, twice weekly and at thosetimes the colonies are scored manually from duplicate wells. At the endof seven days incubation the cells are scored manually from duplicatewells.

Protocol E-1

Protocol is similar to Protocol A except that the cells are plated at4,000 to 10,000 cells per well. At the end of 5 days incubation with theFTI, 1 μL of a 5 mg/ml atock of MTT ( ) was added and the cells wereincubated an additional 4 hours. The media was then removed and thecells were solubilized with 1 ml isopropanol for 2-3 minutes. Theoptical density of the cells was then read at 570 nm wavelength.

Protocol E-2

Protocol is similar to Protocol B except that the cells are plated at4,000 to 10,000 cells per well. At the end of 5 days incubation with theFTI, 1 μL of a 5 mg/ml atock of MTT ( ) was added and the cells wereincubated an additional 4 hours. The media was then removed and thecells were solubilized with 1 ml isopropanol for 2-3 minutes. Theoptical density of the cells was then read at 570 nm wavelength.

Protocol E-3

Protocol is similar to Protocol B except that the cells are plated at4,000 to 10,000 cells per well. At the end of 5 days incubation with theFTI and the antineoplastic agent, 1 μL of a 5 mg/ml atock of MTT ( ) wasadded and the cells were incubated an additional 4 hours. The media wasthen removed and the cells were solubilized with 1 ml isopropanol for2-3 minutes. The optical density of the cells was then read at 570 nmwavelength.

In Vitro Cell Cycle Assay

Cancer cells (MCF-7, MDA-468 or DU-145) are seeded in a 10 cm dish at1,000,000 cells per dish. After one day in growth media, the cells areexposed to various concentrations of a antineoplastic agent along withvehicle (PBS) or 1 μM FTI in the vehicle. After 24 hours of exposure tothe combination or antineoplastic agent, the cells are trypsinized andstained with ethidium bromide. The stained nucleii are analyzed by flowcytometry for evaluation of the DNA content.

In Vivo Tumor Growth Inhibition Assay (Nude Mouse)

Rodent fibroblasts transformed with oncogenically mutated human Ha-rasor Ki-ras (10⁶ cells/animal in 1 ml of DMEM salts) are injectedsubcutaneously into the left flank of 8-12 week old female nude mice(Harlan) on day 0. The mice in each oncogene group are randomly assignedto a vehicle, compound or combination treatment group. Animals are dosedsubcutaneously starting on day 1 and daily for the duration of theexperiment. Alternatively, the farnesyl-protein transferase inhibitormay be administered by a continuous infusion pump. Compound, compoundcombination or vehicle is delivered in a total volume of 0.1 ml. Tumorsare excised and weighed when all of the vehicle-treated animalsexhibited lesions of 0.5-1.0 cm in diameter, typically 11-15 days afterthe cells were injected. The average weight of the tumors in eachtreatment group for each cell line is calculated.

The following dosage groups are utilized to determine the efficacy ofthe combination of the farnesyl-protein transferase inhibitor (FTI) andantineoplastic agent (agent): Group O Vehicle controls Group A: FTI atmaximum no effect dose Group B: FTI at minimal efficacy dose Group C:agent at maximal no effect dose Group D: agent at minimal efficacy doseGroup E: A + C Group F: A + D Group G: B + C Group H: B + D

Additional doses of FTI and agent can be selected as needed.

1. A method for achieving a therapeutic effect in a mammal in needthereof which comprises administering to said mammal amounts of at leasttwo therapeutic agents selected from a group consisting of: a) aprenyl-protein transferase inhibitor and b) an antineoplastic agent. 2.The method according to claim 1 wherein an amount of a prenyl-proteintransferase inhibitor and an amount of an antineoplastic agent areadministered simultaneously.
 3. The method according to claim 1 whereinan amount of an antineoplastic agent and an amount of a prenyl-proteintransferase inhibitor are administered consecutively.
 4. The methodaccording to claim 1 wherein the therapeutic effect is treatment ofcancer.
 5. The method according to claim 4 wherein the therapeuticeffect is selected from inhibition of cancerous tumor growth andregression of cancerous tumors.
 6. The method according to claim 4wherein the antineoplastic agent is selected from: a) amicrotubule-stabilising agent; b) a microtubule-disruptor agent; c) analkylating agent; d) an anti-metabolite; e) epidophyllotoxin; f) anantineoplastic enzyme; g) a topoisomerase inhibitor; h) procarbazine; i)mitoxantrone; j) a platinum coordination complexe; k) a biologicalresponse modifier; l) a growth inhibitor; m) a hormonal/antihormonaltherapeutic agent and n) a haematopoietic growth factor.
 7. The methodaccording to claim 4 wherein the antineoplastic agent is a member of aclass of anti-neoplastic agents, said class selected from: theanthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, the taxanes, the epothilones,discodermolide, the pteridine family of drugs, diynenes, aromataseinhibitors and the podophyllotoxins.
 8. The method according to claim 4wherein the antineoplastic agent is selected from: paclitaxel,docetaxel, epothilone A, epothilone B, desoxyepothilone A,desoxyepothilone B, doxorubicin, carminomycin, daunorubicin,aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycinC, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosinearabinoside, podophyllotoxin, etoposide, etoposide phosphate,teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, estramustine, cisplatin, carboplatin, cyclophosphamide,bleomycin, tamoxifen, ifosamide, melphalan, hexamethyl melamine,thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine,L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide,flutamide, leuprolide, a pyridobenzoindole derivative, an interferon andan interleukin.
 9. The method according to claim 4 wherein theantineoplastic agent is selected from: paclitaxel, epothilone A,epothilone B, desoxyepothilone A, desoxyepothilone B, doxorubicin,daunorubicin, 5-fluorouracil, etoposide, vinblastine, estramustine,cisplatin, ara-C and bicalutamide.
 10. The method according to claim 4wherein the prenyl-protein transferase inhibitor is selected from:2(S)-Butyl-1-(2,3-diaminoprop-1-yl)-1-(1-naphthoyl)piperazine;1-(3-Amino-2-(2-naphthylmethylamino)prop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-{5-[1-(2-naphthylmethyl)]-4,5-dihydroimidazol}methyl-4-(1-naphthoyl)piperazine;1-[5-(1-Benzylimidazol)methyl]-2(S)-butyl-4-(1-naphthoyl)piperazine;1-{5-[1-(4-nitrobenzyl)]imidazolylmethyl}-2(S)-butyl-4-(1-naphthoyl)piperazine;1-(3-Acetamidomethylthio-2(R)-aminoprop-1-yl)-2(S)-butyl-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-[2-(1-imidazolyl)ethyl]sulfonyl-4-(1-naphthoyl)piperazine;2(R)-Butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;2(S)-Butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl)piperazine;1-2(S)-butyl-(2(R)-(4-nitrobenzyl)amino-3-hydroxypropyl)-4-(1-naphthoyl)piperazine;1-(2(R)-Amino-3-hydroxyheptadecyl)-2(S)-butyl-4-(1-naphthoyl)-piperazine;2(S)-Benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)piperazine;1-(2(R)-Amino-3-(3-benzylthio)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;1-(2(R)-Amino-3-[3-(4-nitrobenzylthio)propyl])-2(S)-butyl-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-[(4-imidazolyl)ethyl]-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-[(4-imidazolyl)methyl]-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)acetyl]-4-(1-naphthoyl)piperazine;2(S)-Butyl-1-[(1-naphth-2-ylmethyl)-1H-imidazol-5-yl)ethyl]-4-(1-naphthoyl)piperazine;1-(2(R)-Amino-3-hydroxypropyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;1-(2(R)-Amino-4-hydroxybutyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;1-(2-Amino-3-(2-benzyloxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;1-(2-Amino-3-(2-hydroxyphenyl)propyl)-2(S)-butyl-4-(1-naphthoyl)piperazine;1-[3-(4-imidazolyl)propyl]-2(S)-butyl-4-(1-naphthoyl)-piperazine;2(S)-n-Butyl-4-(2,3-dimethylphenyl)-1-(4-imidazolylmethyl)-piperazin-5-one;2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)piperazin-5-one;1-[1-(4-Cyanobenzyl)imidazol-5-ylmethyl]-4-(2,3-dimethylphenyl)-2(S)-(2-methoxyethyl)piperazin-5-one;2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(1-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-naphthylmethyl)imidazol-5-ylmethyl]-piperazine;2(S)-n-Butyl-1-[1-(4-cyanobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;2(S)-n-Butyl-1-[1-(4-methoxybenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;2(S)-n-Butyl-1-[1-(3-methyl-2-butenyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;2(S)-n-Butyl-1-[1-(4-fluorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;2(S)-n-Butyl-1-[1-(4-chlorobenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)piperazine;1-[1-(4-Bromobenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)piperazine;2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethylbenzyl)imidazol-5-ylmethyl]-piperazine;2(S)-n-Butyl-1-[1-(4-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;2(S)-n-Butyl-1-[1-(3-methylbenzyl)imidazol-5-ylmethyl]-4-(1-naphthoyl)-piperazine;1-[1-(4-Phenylbenzyl)imidazol-5-ylmethyl]-2(S)-n-butyl-4-(1-naphthoyl)-piperazine;2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl)imidazol-5-ylmethyl]-piperazine;2(S)-n-Butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy)imidazol-5-ylmethyl]piperazine;1-{[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl}-2(S)-n-butyl-4-(1-naphthoyl)piperazine;(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(methanesulfonyl)ethyl]-2-piperazinone;(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)ethyl]-2-piperazinone;(R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;(S)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N-ethyl-2-acetamido]-2-piperazinone;(±)-5-(2-Butynyl)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;1-(3-Chlorophenyl)-4-[-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;5(S)-Butyl-4-[1-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-1-(2,3-dimethylphenyl)-piperazin-2-one;4-[1-(2-(4-Cyanophenyl)-2-propyl)-5-imidazolylmethyl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)piperazin-2-one;(S)-n-Butyl-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-1-(2-methylphenyl)piperazin-2-one;4-[1-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-1-(3-chlorophenyl)piperazin-2-one;4-[3-(4-Cyanobenzyl)pyridin-4-yl]-1-(3-chlorophenyl)-5(S)-(2-methylsulfonylethyl)-piperazin-2-one;4-[5-(4-Cyanobenzyl)-1-imidazolylethyl]-1-(3-chlorophenyl)piperazin-2-one;2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-2-methyl-3-phenylpropionyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-4-pentenoyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-4-pentenoyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxypentanoyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxypentanoyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]5-pentyloxy-4-methylpentanoyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-4-methylpentanoyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserinelactone, 2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylbutanoyl-homoserinelactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylbutanoyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine lactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylthio-2-methyl-3-phenylpropionyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine lactone,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentylsulfonyl-2-methyl-3-phenylpropionyl-homoserine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninemethyl ester,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methionine,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methioninesulfone methyl ester,2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-methioninesulfone (Compound 6),2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester,2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyt-methioninesulfone methyl ester,2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-naphth-2-yl-propionyl-methioninesulfone,2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methioninesulfone methyl ester,2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-naphth-1-yl-propionyl-methioninesulfone,2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-methioninemethyl ester.2-(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-methylbutanoyl-methionine,Disulphide of2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-phenylpropionyl-homoserinelactone, Disulphide of2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)-methyl]pentyloxy-3-phenylpropionyl-homoserine,Disulphide of2(S)-[2(S)-[2(R)-Amino-3-mercapto]propylamino-3(S)methyl]pentyloxy-3-methylbutanoyl-methioninemethyl ester 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-Cyanobenzyl)-5-(4′-phenylbenzamido)ethyl-imidazole1-(2′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-Biphenylethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Bromo-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4-(3′,5′-dichloro)-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′-Methoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(3-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4-(3′,5′-Bis-trifluoromethyl)-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)-4-methylimidazole1-(4-Biphenylmethyl)-5-(4-cyanophenyloxy)-imidazole5-(4-Cyanophenyloxy)-1-(2′-methyl-4-biphenylmethyl)-imidazole5-(4-Biphenyloxy)-1-(4-cyanobenzyl)-imidazole5-(2′-Methyl-4-biphenoxy)-1-(4-cyanobenzyl)-imidazole5-(4-(3′,5′-dichloro)biphenylmethyl)-1-(4-cyanobenzyl)imidazole1-(4-biphenylmethyl)-5-(1-(R,S)-acetoxy-1-(4-cyanophenyl)methylimidazole1-(4-Biphenylmethyl)-5-(1-(R,S)-hydroxy-1-(4-cyanophenyl)methylimidazole 1-(4-Biphenylmethyl)-5-(1-(R,S)-amino-1-(4-cyanophenyl)methylimidazole1-(4-biphenylmethyl)-5-(1-(R,S)-methoxy-1-(4-cyanophenyl)-methylimidazole1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(4-biphenyl)-methyl imidazole1-(4-Cyanobenzyl)-5-(1-oxo-1-(4-biphenyl)-methyl imidazole1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-fluoro-4-biphenyl)-methyl)-imidazole1-(4-Cyanobenzyl)-5-(1-hydroxy-1-(3-biphenyl)methyl-imidazole5-(2-[1,1′-Biphenyl]vinylene)-1-(4-cyanobenzyl)imidazole1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene1-(4-Biphenylmethyl)-5-(4-bromophenyloxy)-imidazole1-(3′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4′-Methyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(3′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4′-Trifluoromethyl-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(3′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4′-Chloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′3′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole.1-(2′4′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′5′-Dichloro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(3′-Trifluoromethoxy-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(2′-Fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl) imidazole1-(4-(2′-Trifluoromethylphenyl)-2-Chlorophenylmethyl)-5-(4-cyanobenzyl)imidazole1-{1-(4-(2′-trifluoromethylphenyl)phenyl)ethyl}-5-(4-cyanobenzyl)imidazole 1-(2′-Trifluoromethyl-4-biphenylpropyl)-5-(4-cyanobenzyl)imidazole1-(2′-N-t-Butoxycarbonylamino-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Acetylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Methylsulfonylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Ethylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Phenylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Glycinylaminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole 1-(2′-Methyl-4-biphenylmethyl)-2-chloro-5-(4-cyanobenzyl)imidazole 1-(2′-Methyl-4-biphenylmethyl)-4-chloro 5-(4-cyanobenzyl)imidazole1-(3′-Chloro-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole1-(3′-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3′-Trifluoromethyl-2-methyl-4-biphenylmethyl)-4-(4-cyanobenzyl)imidazole1-(3′-Trifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3′-Methoxy-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Chloro-4′-fluoro-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Ethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-(2-Propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-(2-Methyl-2-propyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2′-Ethyl-4-biphenylmethyl)-5-(4-(1H-tetrazol-5-yl))benzyl)imidazole1-[1-(4-Cyanobenzyl)imidazol-5-ylmethoxy]-4-(2′-methylphenyl)-2-(3-N-phthalimido-1-propyl)benzene1-(3′,5′-Ditrifluoromethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3′,5′-Chloro-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3′,5′-Dimethyl-2-methyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-(N-Boc-aminomethyl)-4-biphenylmethyl)-5-(4-cyanobenzyl)-imidazole1-(3-Aminomethyl-4-biphenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-Cyanobenzyl)-2-methyl-5-(2′-methylbiphenyl-4-yloxy)imidazole5-(4-Cyanobenzyl)-1-(3-cyano-2′-trifluoromethylbiphenyl-4-ylmethyl)-imidazole2-Amino-5-(biphenyl-4-ylmethyl)-1-(4-cyanobenzyl)imidazole2-Amino-1-(biphenyl-4-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Butylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole1-(3-Propylbiphenyl-4-ylmethyl)-5-(4-cyanobenzyl)-imidazole1-(4-Biphenylmethyl)-4-(4-cyanobenzyl-2-methylimidazole1-(4-Cyanobenzyl)-5-[(3-fluoro-4-biphenyl)methyl]imidazole1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)-1-hydroxy]ethyl-2-methylimidazole1-(4-Cyanobenzyl)-5-(4-biphenylmethyl)-2-methylimidazole1-(4-Cyanobenzyl)-5-[1-(4-biphenyl)]ethyl-2-methyl imidazole1-(4-Cyanobenzyl-5-[1-(4-biphenyl)]vinylidene-2-methylimidazole and1-(4-Cyanobenzyl)-5-[2-(4-biphenyl)]vinylene-2-methylimidazole1-(4-[Pyrid-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-[3-Methylpyrazin-2-yl]phenylmethyl)-5-(4-cyanobenzyl)imidazole1-(4-(Pyrimidinyl-5-yl)phenylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole1-(2-[Pyrid-2-yl]pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazoleN-{1-(4-Cyanobenzyl)-1H-imidazol-5-yl)methyl}-5-(pyrid-2-yl)-2-amino-pyrimidineN,N-bis(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzeneN,N-bis(4-Imidazolemethyl)amino-4-[(3-carboxyphenyl)oxy]benzeneN,N-bis(4-Imidazolemethyl)amino-3-[(3-carbomethoxyphenyl)-oxy]benzeneN,N-bis(4-Imidazolemethyl)amino-4-[(3-carbomethoxyphenyl)-oxy]benzeneN-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3-carboxyphenyl)oxy]benzeneN-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-[(3-carbomethoxyphenyl)oxy]benzeneN-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzeneN-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzeneN-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenylthio)benzeneN-Butyl-N-[1-(4-cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzeneN-[1-(4-Cyanobenzyl)-5-imidazolemethyl]amino-4-(phenoxy)benzeneN-(4-Imidazolemethyl)amino-3-[(3-carboxyphenyl)oxy]benzene1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzene(±)-4-[(4-imidazolylmethyl)amino]pentyl-1-(phenoxy)benzene1-[(N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino)methyl]-4-(phenoxy)benzene4-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino]-1-(phenylthio)benzene(±)4-[N-(1-(4-cyanobenzyl)-4-imidazolylmethyl)-N-(n-butyl)amino]-1-(phenylsulfinyl)benzene3-[N-(4-imidazolylmethyl)-N-(n-butyl)amino]-N-(phenyl)benzenesulfonamideand1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino]-3-methoxy-4-phenylbenzene4-{3-[4-(-2-Oxo-2-H-pyridin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile4-{3-[4-3-Methyl-2-oxo-2-H-pyridin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile4-{3-[4-(-2-Oxo-piperidin-1-yl)benzyl]-3-H-imidazol-4-ylmethyl}benzonitrile4-{3-[3-Methyl-4-(2-oxopiperidin-1-yl)-benzyl]-3-H-imidizol-4-ylmethyl}-benzonitrile(4-{3-[4-(2-Oxo-pyrrolidin-1-yl)-benzyl]-3H-imidizol-4-ylmethyl}-benzonitrile4-{3-[4-(3-Methyl-2-oxo-2-H-pyrazin-1-yl)-benzyl]-3-H-imidizol-4-ylmethyl}-benzonitrile4-{3-[2-Methoxy-4-(2-oxo-2-H-pyridin-1-yl)-benzyl]-3-H-imidizol-4-ylmethyl}-benzonitrile4-{1-[4-(5-Chloro-2-oxo-2H-pyridin-1-yl)-benzyl]-1H-pyrrol-2-ylmethyl}-benzonitrile4-[1-(2-Oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile4-[3-(2-Oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile4-{3-[1-(3-Chloro-phenyl)-2-oxo-1,2-dihydropyridin-4-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrileor a pharmaceutically acceptable salt, disulfide or optical isomerthereof.
 11. The method according to claim 4 wherein the prenyl-proteintransferase inhibitor is selected from:(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)

1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;(R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrileand1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzeneor a pharmaceutically acceptable salt, disulfide or optical isomerthereof.
 12. The method according to claim 4 wherein the antineoplasticagent is paclitaxel and the prenyl-protein transferase inhibitor is2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)


13. A method of treating cancer in a mammal in need thereof whichcomprises administering to said mammal amounts of a prenyl-proteintransferase inhibitor and applying to the mammal radiation therapy. 14.The method according to claim 13 wherein the amount of a prenyl-proteintransferase inhibitor and the radiation therapy are administeredsimultaneously.
 15. The method according to claim 13 wherein the amountof a prenyl-protein transferase inhibitor is administered first and theradiation therapy is administered after the prenyl-protein transferaseinhibitor has been administered.
 16. The method according to claim 13wherein the prenyl-protein transferase inhibitor is selected from:2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)

1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;(R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrileand1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzeneor a pharmaceutically acceptable salt, disulfide or optical isomerthereof.
 17. The method according to claim 13 wherein the prenyl-proteintransferase inhibitor is selected from:2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)

or a pharmaceutically acceptable salt, disulfide or optical isomerthereof.
 18. The method according to claim 13 wherein the prenyl-proteintransferase inhibitor is:1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;or a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 13 wherein the prenyl-protein transferase inhibitor is selectedfrom:(R)-1-(3-Chlorophenyl)4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;or a pharmaceutically acceptable salt or optical isomer thereof.
 20. Themethod according to claim 13 wherein the prenyl-protein transferaseinhibitor is selected from:4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrileand or a pharmaceutically acceptable salt thereof.
 21. The methodaccording to claim 13 wherein the prenyl-protein transferase inhibitoris selected from:1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzeneor a pharmaceutically acceptable salt thereof.
 22. The method accordingto claim 13 which additionally comprises administering to the mammal anamount of an antineoplastic agent.
 23. The method according to claim 22wherein the amount of a prenyl-protein transferase inhibitor and theamount of an antineoplastic agent are administered simultaneously. 24.The method according to claim 22 wherein the amount of an antineoplasticagent and the amount of a prenyl-protein transferase inhibitor areadministered consecutively.
 25. The method according to claim 22 whereinthe prenyl-protein transferase inhibitor is selected from:2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)

1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone;(R)-1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl]-2-piperazinone;4-[1-(5-Chloro-2-oxo-2H-[1,2′]bipyridinyl-5′-ylmethyl)-1H-pyrrol-2-ylmethyl]-benzonitrile and1-[N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino]-4-(phenoxy)benzeneor a pharmaceutically acceptable salt, disulfide or optical isomerthereof.
 26. A pharmaceutical composition for achieving a therapeuticeffect in a mammal in need thereof which comprises amounts of at leasttwo therapeutic agents selected from a group consisting of: a) aprenyl-protein transferase inhibitor and b) an antineoplastic agent. 27.The pharmaceutical composition according to claim 26 comprising anamount of a prenyl-protein transferase inhibitor and an amount of anantineoplastic agent.
 28. The pharmaceutical composition according toclaim 26 wherein the therapeutic effect is treatment of cancer.
 29. Thepharmaceutical composition according to claim 26 wherein the therapeuticeffect is selected from inhibition of cancerous tumor growth and theregression of cancerous tumors.
 30. The composition according to claim27 wherein the antineoplastic agent is paclitaxel and the prenyl-proteintransferase inhibitor is2(S)-[2(S)-[2(R)-Amino-3-mercapto]-propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methioninesulfone isopropyl ester (Compound A)


31. A method of preparing a pharmaceutical composition for achieving atherapeutic effect in a mammal in need thereof which comprises mixingamounts of at least two therapeutic agents selected from a groupconsisting of: a) a prenyl-protein transferase inhibitor and b) anantineoplastic agent.
 32. The method of preparing a pharmaceuticalcomposition according to claim 26 comprising mixing an amount of aprenyl-protein transferase inhibitor and an amount of an antineoplasticagent.